of · analysis of the data. ... Case history report fom. ... 1 995; Hooisma, Hanninen, Emmen &...
Transcript of of · analysis of the data. ... Case history report fom. ... 1 995; Hooisma, Hanninen, Emmen &...
Matemal Occupational Exposure to Organic Solvents During Pregnancy
and Subsequent Visual and Cognitive Development in the Child:
A Prospective Controlled Pilot Study
Christine Siambani
A thesis submitted in conformity with the requirements
for the degree of Master of Arts
Graduate Department of Psychology
University of Toronto
@ Copyright by Christine Siambani (2000)
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Absmct
This prospective study evaluated the effects of prenatal exposure to organic solvents (OS) on
visuai and cognitive hinctioning. Children (n=33) whose mothen worked with OS during
pregnancy were matched with a referent group (n=28) on age, gender, ethnicity. matemal
education, and socioeconomic status. Groups wen compared on psychological tasks and
measures of colour vision and visual acuity. Workplace exposure was assessed by interviews
at time of initial contact during pregnancy. Prenatal solvent exposure was associated with
significant group differences on expressive language ( ~ ~ 0 . 0 1 ) and graphomotor ability
(pcO.05) adjusted for covariates. Visual test findings revealed significantly more deficits in
blue-yellow ( ~ ~ 0 . 0 1 ) and red ( ~ ~ 0 . 0 5 ) colour discrimination, as well as poorer visual acuity
(peO.05) among solvent exposed children. Frequency of colour vision loss in the exposed
group was greater than the expected rate in the general population. The findings suggest that
prenatal exposure to OS is associated with subsequent functional changes to
neurodevelopment.
Acknowledgements
This research was supported in part by the National Science and Engineering
Research Council of Canada, The Hospital for Sick Children Research Institute's Trainee
Start-Up Fund, and the Physicians Services incorporated (Ontario, Canada).
This thesis could not have been written without the aid of research associates and
menton who have betn a source of inspiration for me. I thank Patrick Arseneau and Rachel
Greenbaurn for their testing assistance and enthusiasm thmughout the study. 1 equally thank
Moira Myszak for her helpful suggestions in helping me plan the study, Alice Chiu and
Janice Wong for their dedicated effon in scoring results for reliability purposes. I am
indebted to Dr. Carol Westall and Carol Panton for their continued support and for sharing
their equipment, expertise, and space for my study. The colour vision test could not have
been included in this study without Dr. Westall's supervision and knowledge of effective
diagnostic tests for children. Thanks also to Dr. F. Vaccarrino for his contributions as my
subsidiary advisor, and Derek Stephens for his valuable input regarding the siatistical
analysis of the data. I owe Dr. Gideon Koren my deepest gratitude for his continued
enthusiasrn about my research, and for his professional advice regarding the planning of the
study. I am especially grateful to Mark Till for al1 of his help and continuous support
throughout this study. Finally, without the encouragement, patience, high standards, and
endless houn of helpful discussion of Dr. Joanne Rovet, it would not have been possible to
put this thesis into its fmd form. I sincerely thank al1 those who made this possible.
iii
Table of Contents
......................................................................... 1 . Introduction ............................... ... - 1
..................................... Organic Solvent Physical and Chemical Characteristics 4
.......................................................... Maternai Exposure. intake and Excretion 4
......................................................... Prenatal Absorption of Organic Solvents 7
Adverse Pregancy Outcornes h m Matemal Exposure to Solvents ............... 8
....................................................................... Objectives of Proposed Study 14
. . S peci fic Prediction ......................................................................... 15
2 . Method
. . ........................................................................................................ 2.0 1 Participants 16
......................................................................................................... 2.02 Procedure 18
.................................................................................... 2.03 Statistical Analyses 28
3 . Results
.............................................................................. Demographics 31
................................................................ Developmental Evaluation 33
........................................................................... Visual Functions 34
....................................................................... Cognitive Abilities -37
................................................................................................ Discussion 43
................................................................................................ Re ferences 61
..................................................................................................... Tables 74
................................................................ ..................... Figures .. ... ... 90
Appendices .................................................g..*... 94 ..................................
List of Tables
Table 1. Ordering of tests for children aged 3 to 5 yean.
Table 2. Ordering of tests for children aged 5 to 7 years.
Table 3. Distribution of occupations and type of solvent exposure.
Table 4. Demographic information of the study women and their children.
Table 5 . Developrnental milestones (in monîhs) for exposed and control groups.
Table 6. Measures of growth for both exposed and control groups.
Table 7. Maternai ratings of child's intemalizing and extemalizing behavioun.
Table 8. Frequency (in percentage) of binocular scores on the Minimalist test for exposed
and control groups.
Table 9. Frequency (in percentage) of averaged monocular scores on the Minimalist test
for exposed and control groups.
Table 10. Domain scores for exposed and control groups presented as z-scores.
Table 1 1. 2-scores for the verbal ability subtests.
Table 12. Summary of multiple ngression analyses (foward model) of the effects of
prenatai exposure to organic solvents on tasks of language ability.
Table 13. 2-scores for the visuo-spatial subtests.
Table 14. 2-scores for the visuo-motor subtests.
Table 15. Sumrnary of multiple regression analyses (forward model) of the effects of
prenatal exposurc to organic solvents on graphornotor ability.
Table 16. 2-scores on tasks of attention.
Figure 1.
Figure 2.
Figure 3.
Figure 4.
List of Figures
Mean T-score values on nanow band syndromes of the CBCl for exposed (solid)
and control (hatched) groups.
Binocular and monocular colour discrimination score as assessed by the Minimalist
test for each colour confusion line. The plots show mean colour vision score (I SE)
for the exposed (n=32) and control (n=27) group. The y-axis indicates the cap
number successfully identified. A value above one represents an error in colour
discrimination and a value of one represents a perfect sccre.
Frequency (in percentage) of binocular colour discrimination scores on the
Minimalist test for exposed and control groups. A score of 1 represents correct
identification of the lest saturated colour chip. A score above I represents a colour
discrimination deficit ranging fiom mild loss (Le. score of 2 or 3) to severe (Le.
score of 4 and above).
Binocular and averaged monocular rnean visual acuity (f SE) as assessed by the
Cardiff Car& at 1 meter viewing distance. The plot shows the results for the
exposed (n=29) and control (n=24) groups. The y-axis gives the acuity in logMAR,
where MAR is the minimum annle of resolution in minutes of arc.
Appendix A.
Appendix B.
Appendix C.
Appendix D.
-4ppendix E.
Appendix F.
Appendix G.
Appendix H.
Appendix 1.
Appendix J.
Appendix K.
Appendix L.
Appendix M.
List of Appendices
Research information fonn.
Research consent fom.
Outcome of follow-up.
Motherisk intake form.
Case history report fom.
Social strata for the Hollingshead Four-Factor Index of Socioeconomic status.
Sample FACES questionnaire.
Ranges of Family Adaptability and Cohesion Evaluation Scales (FACES).
Test protocol for young children (aged 3 - 4 years).
Test protocol for older cohort of children (aged 5 - 7 years).
Normal acuity ranges for the CardiRCards by age.
Case history: Matemal occupation solvent exposure information
Matemal report of exposure information obtained at time of pregnancy
(before) and at time of study (1 999).
vii
lntroduc tion
A large number of women are exposed to organic solvents (OS) in the workplace
(Jones & Balster, 1998), many of whom will continue to work throughout pregnancy.
Adverse reproductive health outcornes caused by matemal occupational exposure to OS
duing pregnancy range from menstnial disorders (Lindbohm, 1995) to an increased nsk of
spontaneous abortions (Holmberg, 1979; Taskinen, Lindbohm & Kemminki, 1986) and birth
defects in the O ffspring (Tikkanen & Heinonen, 1 988; Lindbohm, Taskinen, Sallmen &
Hemminiki, 1990; McMartin, Chu, Kopecky, Einarson & Koren, 1998; Khattak, et al., 1999).
These cm occur as a result of exposure to a single substance or a combination of toxic
substances in the workplace.
While abnormal central nervous system (CNS) hctioning of the fetus is also a likely
consequence of prenatal solvent exposure, very few studies have examined long-term effects
of matemal solvent exposure (Eskenazi, Gaylord, Bracken & Brown. 1988; Kersemaekers,
Roeleveld &Zeilhuis, 1995). Of the studies conducted, most have placed greater emphasis on
basic teratology (i.e. offspring viability, morphology, growth) than offspring behaviour. As a
result, we are faced with an incomplete database for safety assessrnent because many OS, for
which there is basic teratology data, lack measures of sensory and behaviod functioning.
This lack of information is of concem because lower doses of OS, such as those cornmonly
found in the workplace, may induce more subtle manifestations of toxicity in the absence of
physical malformations. Furthemore, functional deficits can occur after the time for
malformations while the brain is still developing.
A starhg point for understanding the long-teim effects of prenatal exposuie to OS can
be sought h m past studies in adults exposed occupationaily to OS. In contrast to the paucity
of information on the neurotoxic effects of prenatal exposure, the effects of occupational
exposure to OS in adults have been well studied. One particularly useful marker of early CNS
dyshinction following neurotoxic exposure in adults is visual h t ioning. Previous studies
have demonstrated that continued exposure to a wide range of OS at levels encountered at the
workplace can produce visual deficits including acquired dyschromatopsia (Raitta et al., 198 1;
Horan et al., 1985; Mergier, Blain & Lagacé, 1987; Mergier et al., 1996; Gobba et al., 1% 1;
Gobba, Cavalieri, Bontadi, Tom & Dainese, 1995; Fallas, Fallas, Maslard & Dally, 1992;
Campagna et al., 1995, Carnpagna et al., 1996, Muttray, Wolters, Jung & Konietzko, 1999),
modi fied electroretinal responses (Blain, Lachapelle & Molotchniko ff, 1994). reduced
contrast sensitivity threshold (Mergler, 1995), decreased visual acuity, optic neuritis, and
vision b l h n g (reviewed in Boyes, 1992). Chromatic discrimination is particularly sensitive
to the subtle effects of neurotoxic exposure because changes to colour vision are not
necessarily accompanied by functional disorders. Because changes in colour vision may be
more easily detectable before overt symptoms manifest, testing chromatic discrimination
capacity may constitute an important early indicator of neurotoxic darnage in children exposed
in utero to OS.
The effects of exposure to OS on cognitive functioning is another area well researched
in adults. Numerous studies have associated occupational solvent exposure with adverse
effects on psychological and neurological functioning. The studies covered groups such as
housepainters (Lundberg et al., 1 995; Hooisma, Hanninen, Emmen & Kulig, 1 994), tiberg lass
builders (Cherry et al., 1980; Mutti et al., 1984; Tsai and Chen, 1996; Jegaden, Amam,
Simon, Legoux & Galopin, 1993), industrial painters (Elofsson et ai., 1980; Linz et al., 1986;
Kishi, Harabuchi, Katakura, Ikeda & Miyake, 1993; Ruijten et al., 1994) and workers in
Prcnatal Exposurc ta Organic Solvents 3
reinforced plastics industry (Lindstrom, HkkOnen & Hemberg, 1976; HbkOnen, Lindstrorn,
Seppalainen, Asp & Hemberg, 1978; Cherry, Rodgers, Venables, Waldron & Wells, 198 1 ;
Matikainen, Forsman-Gionholm, P f m i & Juntunen, 1993; Mergler et al.. 1996), paint
(Fidler, Baker & Letz, 1987; Lee & Lee, 1993; Colvin, Myers, Nell, Rees & Cronje. 1993) or
adhesive factones (Escalona, Yanes, Feo & Maizlish, 1995). Workers exposed ?O OS have
show impairments in one or more of the following f'unctional areas: attention, executive
function, short-tem memory, verbal fluency, motor abilities, visuo-motor and visuo-spatial
skills, as well as poorer performance on tasks of leaming. Given the well documented effects
on neuropsychological and neurological functioning in adults exposed to OS, studies should
focus on the potential fùnctional deficits in children exposed to OS in utero.
Based on past studies, we see that OS have an &ni@ For the nervous systern and are
linked to visual and cognitive deficits in adults. Given that the fetus is highly susceptible to
neurotoxic insult, it is likely that prenatal solvent exposure will affect its neurodevelopment.
Thus, the following question was posed: What are the effects of matemal occupational
exposure to OS during pregnancy on visuai and cognitive development in the offspring? This
question was investigated by (a) reviewing the evidence linking abnomal development of the
fetus to matemal solvent exposure, (b) designing a snidy to investigate the effects of prenatal
exposure to OS on visual and cognitive development, and (c) testing the experimental
hypotheses using a prospective controlled design. Based on the results of the current snidy,
preliminary evidence of adverse developmentd outcornes associated with materna1
occupationai exposure to OS is presented. As well, methodological issues related to this area
of research are addressed.
The tenn "organic solvent" refers to a generic classification for a chemical compound
or mixture used to extract, dissolve or suspend non-water soluble materials (Arlien-Sobgrg,
1992). Most OS are liquids that boil in the range of 7S°C to 220°C and have structurally
diverse, low rnolecular weight physiochemical properties. Solvents are physicaily
charactenzed as volatile, lipophilic, and highly soluble. They are grouped according to their
chemical structures. These include: hydrocarbons, which are divided into the aliphatic
hydrocarbons (e.g. hexanes, pentanes, octanes) and the ammatic hydrocarbons (e.g. berizene,
styrene, toluene, xylene); halogenated compounds (e.g. carbon tetrachloride. methylene
chlonde, trichloroethy lene, perchloroethylene); alcohols (e.g. methanol. ethanol); gl yco 1s (e.g.
ethylene, propylene glycol); ketones (e.g. methyl ethyl ketone) and complex solvents (e.g.
petroleurn ethen, cubber solvent, varnish, painters' naphtha, minera1 spirits). Understanding
these basic structures may allow us to extrapolate data on one solvent to another one that is
c hemically similar.
Matemal exposure to OS is widespread. It can occur in the workplace, through
household product use, environmental pollution and tobacco smoking. Occupations with
potential chemical exposures include laboratory technicians, graphic designers, painters, hair
dressers, photo developers, dry cleaners, and workers in clothing and textile industries.
Solvents are also used by manufacturers of paints, glues, coatings, dyes, and polymers, as well
as in the preparation of pmcessed foods and phannaceuticals. In household producis, OS are
Prenatal Exposurc to Organic Solvents 5
found in spray adhesives, spray paints, oil paints, varnishes, nail removers and felt-tip pens.
In environmental pollution, OS have been reported as a contaminant in drinking water
(Witkowski & Johnson, 1992). and as air pollution (Marshall, Gensburg, Deres & Cayo,
1997). Toluene is also inhaled through tobacco smoking. It has been reported that smokers
inhale 80 to 160 pg toluene per cigarette and have approximately a onefold increased
concentration of toluene in blood (median 2.0 pgL) cornpared to nonsmokers (median 1 . i
pg/L) (cited in von Euler, 1994). Another common route of solvent exposure that is on the
rise today is deliberate exposure in pursuit of an intoxicating solvent "high" (Henh, Podnich.
Rogers & Weisskopf, 1984; Jones & Balster, 1998). According to a national survey of high
school students in the United States, approximately 17% of adolescents have sniffed inhalants
at leasi once in their lives (Johnston, Malley & Bacban, 1994 cited in Jones & Balster,
1998).
Certain properties of OS affect exposure intake. Solvents that are both lipid and water
soluble can pass through intact skin most easily because skin has both water and lipid
compartments. Because of their volatility, OS cm also easily enter the bloodstream through
the alveoli of the Iungs. Measures of solvent inhalation show that between 40 to 80% of the
inhaled dose is absorbed at rest. The total amount absorbed increases with exercise and
pregnancy as blood flow to the lung and alveolar ventilation increases (Welch, 1993). Once
the OS are absorbed, they are immediately distributed throughout the body with high affinity
for lipid-nch tissues such as myelin or white rnatter in the brain.
Metabolism and excretion kinetics are highiy variable arnong compounds. Matemal
excretion of unchanged OS occurs primarily through the Lungs as expired air or they may be
metabolized in the liver and eliminated in the urine. The biological half-life of OS is typically
in the range of several hours (Baker, Smith & Landrigan, 1985) making the timing of sample
collection relative to the termination of exposure critical for reliable estimates of uptake. A
solvent with a half-life longer than 12 hours will accumulate over the work week, resulting in
a higher body hurden at the end of the week fiom the same exposure conditions. A detailed
description of the excretion kinetics and biotransformation reactions that influence the fate of
absorbed OS is beyond the scope of this review.
nie amount of OS retained is dificult to quanti@ because it is dependent on several
solvent- and human-related factors. Solvent-related factors incfude: the level and duration of
exposure, specific physiochemical features of each solvent, the use of protective equipment,
and synergistic effects of sirnultaneous exposure to solvent mixtures (reduced rate of
metabolism of one solvent in the presence of other OS) (Baker et al., 1985). With respect to
human-related factors, physiological Factors such as body build, percentage body fat, blood
and tissue solubility affect the pharmacokinetic profile of OS (Sato, Endoh, Kaneko &
Johanson, 199 1). Toxicity of OS also varies according to levels of physicai exercise
(associated with increased pulmonary capillary blood flow), diumal metabolic cycles, and
alcohol use (Cherry, 1993). Baker et al. (1985) reported that ethanol ingestion decreases the
metabolic clearance rate of xylene by about one half-life. This is due to a metabolic
interaction betwecn xylene and alcohol which are degraded by the sams cnzyme (aldehyde
dehydrogenase). As a result of the ethanol-induced metabolic inhibition, concurrent exposure
to alcohol and OS slows clearance of the solvent and might be expected to prolong internai
exposure to the neurotoxin. Thus, biological monitoring alone cannot detennine that an
Prenatal Exposure to Organic Solvents 7
exposure is safe or without reproductive risk. Exposure estimates obtained by biological
monitoring must be combined with adequate health data to determine risk.
It is important to note that many factors can affect the rate of transfer of drugs and
chemicals fiom matemal blood to the fetus. These include: the degree of lipid solubility and
protein binding, the pKa of the compound, placentai blood flow, placental function, and the
degree to which active transport occurs (cited in Welch, 1993). As a general nile. compounds
that have a high aflinity for lipid, a low degree of ionization, and a molecular weight less han
1000 are rapidly transfened across the placenta. Since OS fit this description by definition,
many OS can cross the placenta1 barrier into the arnniotic fluid where they are ingested and
dermally absorbed by the conceptus.
Studies in both animals (Stoltenburg-Didinger, Altenkirch & Wagner, 1990) and
humans (Laham, 1970) have exarnined transplacental dimision of OS. In one study of
pregnant mice, placenta1 transfer of radiolabeled toluene, xylene, and benzene was studied
using autoradio-graphic and liquid scintillation rnethods (Ghantous & Daneilsson, 1986 as
cited in Valciukas, 1994) and the distribution of the OS and their metabolites was obsewed at
difFerent time intervals after a ten minute period of solvent inhalation. Results showed that
irnmediately after inhalation, the OS reached high concentrations in the mothers' lipid-rich
tissues (i.e. brain and fat) and in perfùsed organs such as the liver and kidney. M e r one hou,
these were eliminated h m al1 matemal tissue except fat. Metabolites reached peak levels
between 30 minutes and one hou fier inhalation and were eliminated rapidly thereafter. It is
important to note that at dl stages of gestation, placental m s f e r of aonmetabolized OS was
Prcnatal Exposurc to Organic Solvents 8
observed in the fetus and in amniotic fluid immediately, and up to one hou after matemal
inhalation.
The fetus is considered especiaily vulnerable to CNS insult for severai reasons. First,
the incomplete development of the blood-brain barrier makes the fetus more susceptible to
neurotoxic insult. Second, the fetus is at increased risk due to the relatively high lipid content
of the developing brain compared to the rest of the body. niird, based on phwnacokinetic
concepts, the mechanisms for detoxification are not fùnctioning due to immaturity of the
necessary organs for solvent metabolism. Thus, due to a number of characteristics inherent in
the biological system, the fetus is more vulnerable to toxic substances.
Animai studies have reported lhat a variety of OS cross the placenta resulting in
increased embryotoxicity (reflected by lower conception rates and smaller litter size),
miscamiage, and structural abnormalities (Stoltenburg-Didinger et al., 1990). Malformations
following prenatal solvent exposure in animals include hydrocephaly, exencephaly, skeletal
defects, and cardiovascular abnormalities (Stolenburg-Didinger et al., 1990; Schwetz et al.,
1992; Narotsky & Kavlock, 1995; Kishi, Chen, Karakura, ikeda & Miyake, 1995; Thel&
Chahood, 1997). A delay in the maturation of the cerebellar cortex (Stolenburg-Didinger et
al., 1990) and changes to the lipid class composition of the cerebral cortex have also been
reported (Kyrklund, Alling, Haglid & Kjellstand, 1983). Studies of behavioural toxicity in the
O ffspring of animals following matemal exposure to OS have revealed significant dose-
dependent efflects such as delayed mflex and motor development (Kishi et al., 1995), altered
rates of behaviourel habituation to novel environments (Bomschein, Hasting & Manson,
Prenatal Exposure to Organic Solvents 9
1980), deficits in spatial learning and memory (von Euler, Ogren, Li, Fwte & Gustafsson,
1993), and increases in spontaneous activity (Kishi et al., 1995). Interestingly, these effects
were observed in the absence of overt matemal toxicity.
Matemal exposure to OS in the workplace has been associated with various disorden
of reproductive health including reduced fertility and menstnial disorders (Lindbohm, 1995).
Reduced fertility in animals and humans is rnost clearly associated with exposure to glycol
ethen and their acetates. Menstrual disorders, on the other hand, are most commonly
associated with exposure to benzene, toluene, xylene, styrene, carbon disulfide, and
fomaldehyde. Matemal occupational exposure to OS during pregnancy has also been
associated with increased rates of spontaneous abortion (Hemminki, Franssila & Vanio, 1980;
Taskinen, Lindbohm & Hemminki, 1986), but not al1 studies have confirmed this association
(Axelsson, Lutz & Rylander, 1984). Other studies have focused specifically on congenital
malformations (Le. cle A palate, cardiovascular malformations) following prenatal solvent
exposure Ofolmberg & Nminen, 1980; Blomqvist, Encson, Kallen & Westerholm. 198 1 ;
Hemrninki, Mutanen, Salonieni & Luoma, 198 1 ; Holmerg & Kurppa, 1982; Kurppa et al.,
1983; McDonald, Lavoie, Cote & McDonald, 1987; McDonald et al., 1 988; Tikkanen &
Heinonen, 1988; Lindbohm et al., 1990; Kersemaekers et al., 1995; Khattak et al., 1999). In a
recent meta-analysis (McMartin et al., 1998), an increased risk of major malformations and a
trend towards spontaneous abortions were detected in pregnancy outcome following matemal
exposure to OS. In another study (Lindbohm, 1995) children whose mother's were exposed
to OS during pregnancy were reported to have higher incidences of leukemia and brain Nmon
than nonexposed chilchen. It is important to note that these adverse effects have been
Prenatal Exposurc to Organic Solvents 10
observecl even in mothers exposed to OS near or below the standard occupational exposure
levels (von Euler, 1994).
In general, studies in humans and animals pmvide evidence of an association between
solvent exposure during pregnancy and congenital defects in the offspring. in the human
studies, however, it is nearly impossible to identify a specific solvent responsible for the
increased risk of an adverse outcome because most of these studies involved populations
occupationally exposed to a mix of OS. Because the level of exposure in human teratology
studies is usually unknown, it is difficult to determine which occupations are at increased risk.
Based on the current data, women should be advised to minimize exposure to OS dunng
pregnancy. This exposure reduction must occur early in pregnancy to prevent effects during
critical penods of organogenesis, and should extend throughout pregnancy to protect the
developing organism.
The fact that numerous OS are ubiquitous in the environment has also raised
considerable attention over the potentiai for teratogenesis. In a study by Marshall et al.
(1 997), an elevated risk for CNS and musculoskeletal defects was found among offspring of
women exposed to OS fiom hazardous waste sites during pregnancy. This association shows
that fietal neurodevelopment may be disrupted even by indirect exposure to OS in the form of
pollution. In another study, Witkowski and Johnson (1992) investigated the association
between organic solvent water pollution and low birth weight in Caucasian residents in
Michigan. Results showed a positive relationship between water pollution caused by benzene
and chlorinated solvents and per cent of low-weight births. Although these correlations do not
si@@ causation, there is reason for concem that environmental pollution rnay be linked to
Prcnatal Exposure to Organic Solvents 11
epidemics of birth defects. However, this relationship should be explored in greater detail in a
prospective rather than retrospective study design, in order to have a more accurate record of
pollution during pregnancy.
inhalation ofpaint or glue is a popular fonn of recreational dmg abuse, particularly
arnong teenagers and young adults. Toxic effects resuiting from chronic solvent abuse
include: cerebellar degeneration, cortical atrophy, impaired mental and intellectual
performance, and in some cases, sudden death fiom suspected cardiac arrythmias (Hersh,
Podmch, Rogers & Weisskopt 1984). Patients suffenng h m chronic abuse of toluene also
show optic neuropathies and changes in electroretinograms (Toyonaga, Adachi-Usami &
Yarnazaki, 1989 as citrd in Muttray et al., 1999). Matemal complications of toluene abuse
during pregnancy include renal tubular acidosis, hypokalemia, hypocalcernia, cardiac
antiythmias, rhabdomyolysis, and premature labour (Arnold, Kirby, Langendoerfer &
Wilkins-Huang, 1994). Teratogenic effects in children bom to mothen addicted to OS dunng
pregnancy have shown similarities to those with fetal alcohol syndrome (Pearson, Hoyme,
Seaver & Risma, 1994)'. Abnomal features include microcephaly, a Bat nasal bridge, a
hypoplastic mandible, short paipebral fissures, mildiy low-set ears, a sloping forehead, and
uncoordinated arm movements (Hersh et al., 1984). Analysis of the pattern and nature of
associated mal formations suggests a deficiency of cranio facial neuroepitheli um and
mesoderrnal components due to increased embryonic ce11 death (Pearson et al., 1994).
Neurobehavioural effeçts observed in children exposed to solvent-sni ffing mothen include
' This is no< surpcising given that alcohol is a type of rolvcnt.
Prcnatal Exposure to Organic Solvents 12
delayed development with greater language deficits, hyperactivity, and attentional problems
(Hersh et al., 1984). It should be noted, however, that studies of children with toluene
embryopathy are ofien confounded by exposures to other potential teratogens including
alcohol, cocaine or heroin.
One prospective study by Eskenazi, Gay lord, Bracken and Brown (1 988) compared
the neurobehavioural development of forty-one 3.5 year-old children exposed to OS in utero
with that of age- and gender-matched children whose mother's were not exposed to OS.
Children's development was evaluated directly using the McCarthy ScaIes of Children's
Abilities and by parental report includhg the Childhood Personaiity Scale and Conners Parent
Hyperactivity Rating Scale. Results showed no significant differences in cognitive stanis o n
any of the McCarthy scales, nor in parental ratings of the child's personality. Eskenazi et al.
suggested a number of factors that could explain this lack of significant differences. First, the
study had inadequate power because of insufficient sample size. Second, insensitivity of the
outcome measures may have rnissed some differences between the solvent-exposed and
control group or it is also possible that the offects do not emerge until a later age when more
complicated cognitive skills such as reading develop. W d , the exposure levels in this study
may have been too low to produce noticeable neurobehavioural deficits. However, analysis of
the mothers' reports of their child's developmental milestones revealed a significant temporal-
response relationship. Results showed that increasing length of exposure was related to older
ages at which the children began to walk, but this effect was not found for the other
developmentai milestones.
Prenatal Exposurc to Organic Solvents 13
In another study by Kenemaekers et al. (1997)' the neurodevelopment in offspring
exposed to OS in utero was investigated using a large historical cohort of hairdressen in The
Netherlands. Nine thousand hairdressen were age-matched with 9000 clothing sales clerks
who served as the reference gmup. Women completed a questionnaire on their reproductive
history, including questions on the ages of their child's developmental milestones, and the
occurrence of seizwes during Bver. Results showed significmt delays in speaking Tint words
and first sentences among children of hairdressers boni between 1986 and 1988, but not
among those bom between 1 99 1 and 1 993. Seizures during fever had occurred more O ften
among children of hairdressers for both study periods. The results of this explorative study
indicate more adverse neurodevelopmental effects among offspnng of hairdressers in the
earlier (1 986 to 1988) compared to the later period (1991 to 1993). This difference was
suggested to reflect changes in chemicals used by hairdressen over tirne.
To date, very little is known about the effects of matemal occupational exposure to OS
on neurobehavioural functioning in the offspring. Most of the research in this area has
focused on pregnancy outcome or the incidence of major malformations. Although it is very
important to know the risk of major malformations, this approach is of questionable value in
identifying the effects of minor, and usually long-tenn exposure to OS. Nevertheless, thete is
reason for concem that prenatal exposure to OS may be associated with subtle changes to the
developing CNS. There is a need for considerable work, employing continuous measures of
behaviour, to evaluate effects of prenatal exposure to OS on the developing CNS at dosages
below those that pmduce death or visible anomaly.
ves of SQ&
The primary objective of the present study was to investigate whether matemal
occupational exposure to OS during pregnancy is associated with changes to cognitive and
visual development in the o f f s p ~ g . The specific focus on the occumnce of colour vision
deficits was prompted by the observation that low-level exposure to OS cm cause changes to
the ntina and optic nerve in workers exposed to OS. Since the development of the visual
system begins in the first trimester, it was predicted that matemal exposure to OS during
pregnancy will disnipt normal visual development in the offspring. These changes were
predicted to result in long-term perturbations on overall colour vision and visual acuity.
Prenatal exposure to OS was also expected to impair cognitive functioning as a result of subtle
alterations in early bnin development. In this study, a broad neuropsychological repertoire
was used to assess cognitive outcome in young children exposed to OS in utero. The test
battery included tasks shown in the research literature on adults to be sensitive to solvent
exposure. The specific cognitive abilities evaluated in this study included language. attention.
visuo-spatial and visuo-motor skills.
The research approach of the current study involved a prospective controlled design.
This type of design is preferred because it avoids many of the problems associated with
retrospective designs. For example, data collected retrospectiveiy may be confounded with
memory bias reflecting outcome ofpngancy (Bar-Oz, Moretti, Mareels, Van Tittelboom &
Koren, 1999). In other words, the mother of a child with a behavioural problem may actively
try ta recall events that lead to the deficit, whereas the mother of a healthy child is more likely
to forget any potentially hannfùl exposuns during the pregnancy. Thus, use of prospective
Prenaîal Expom to Organic Solvents 15
data offers a more reliable source of exposure information that cm be used to address
questions about childfen' s fùnctioning following prenatal exposure to OS.
This study addnssed the following specific questions: (1) Does prenatal exposure to
OS affect colour vision and visual acuity? (2) What is the impact of prenatal solvent exposure
on language, attention, visuo-spatial and visuo-motor ability? and (3) What is the relationship
between the dose of exposure and the incidence of adverse developmental effects? In addition
to measures of visual and cognitive functioning, this study assessed growth of child,
developmental milestones, and child problem behaviours using self-administered
questionnaires completed by the mother. Finally, methodological issues related to this area of
research are discussed.
It was hypothesized that children exposed to OS in utero would show deticits in colour
vision and visual acuity compared to a sample of matched controls. Given the predicted effect
of damage to the visual system in solvent-exposed children, more deficits were expected to
occur on tasks of visuo-motor and visuo-spatial ability than on tasks of language and
attention. A dose-response relationship was predicted with poorer performance in children
whose mothers were exposed to higher levels of OS. Finally, a temporal-response
relationship was expected with more deficits associated with increasing length of exposure to
OS*
Prenatal Exposure to Organic Sotvents 16
Method
Al1 participants were recruited from the Motherisk Program, a consultation service for
teratogenic exposure during pregnancy at The Hospital for Sick Children in Toronto, Ontario.
The study cohort consisted of 6 1 children aged 3 to 7 years whose mother's had been
counseled between 1992 and 1996 by the Motherisk Program, Ali women were contacted
through an initial phone cal1 by the experimenter who explained the purpose of the study.
Women interested in the study were sent a description of the research (see Appendix A)
followed by another phone cal1 to discuss any questions. Children whose parents agreed to
participate came to The Hospital for Sick Children for a full rnoming or full aftemoon session.
Al1 children were tested between March 1999 and October 1999. The protocol for the study
was approved by the Research Ethics Board at The Hospital for Sick Children. Informed
consent fiom the parents was obtained at the time of testing in accordance with the Research
Ethics Board (see Appendix B).
Between 1992 and 1996, 1 17 women who lived within a 4-hou dnving radius of
Toronto contacted the Mothensk Pmgram with regard to occupational exposure to OS. Of the
L 17 women, 65 were successfùlly contacted and screened by telephone while 52 were lost to
follow-up. Fifteen of the women contacted were excluded for the following reasons:
pregnancy resulted in miscarriage (n=4), premature bhth (n=l), removed themselves nom the
exposure (n=3), autistic child (n=l), endocrine disorders (n=2), depmsion during pregnancy
(a=l), exposed to teratogens other than OS (n=2), and did not speak English (n=l). The
remaining 50 women were mailed a package that Ulciuded a letter describing the purpose of
the study, methodological information and several questiomaires. Shortly thereafter, women
were contacted again by phone and asked if they were interested in participating with their
child in the study. Thirty-five women agreed to participate. Of the 35,2 women missed their
appointments and then lost interest, leaving 33 women in the final group. Since 4 women
were occupationally exposed to organic solvents for more than one pregnancy, the sample of
children in the exposed group consisted of 37 subjects. Of the 37 children tesied, the data
from 4 were subsequently excluded for the following reasons, some of whch were not
disclosed at the initial phone interview: mother used recreational dnigs during pregnancy
(n-1 ), premature birth (n=2), mother had surgery at 2 months of pregnancy (n=L ). The final
sample of children in the exposed group consisted of 33 subjects with a rnean age of 4.6 * 1.17. Colour vision data was omitted fiom the analysis for one child due to congenital colour
vision defects.
Mothea and their children in the solvent-exposed group were matched with a referent
group of 27 mother-child pain on age (a months), gender, ethnicity, parental marital and
socioeconomic status. Referent mother-child pain were recruited fiom a database of wornen
who had contacted Mothensk for exposure to a non-teratogenic agent during pregnancy. A
non-teratogen is defined as a medicinal or environmental substance that has not been
associated with a specific risk of major malformations, miscimiage or abnormal neurological
development. The database consisted of 80 women who were interviewed by phone to ensure
they met the criteria for inclusion as a referent subject. Of the 80 woman contacted, 70 met
the cnteria for inclusion as a referent subject. During this initial contact, women were asked
questions about their child and farnily socioeconornic status for the purpose of matching.
Women were mbsequentiy contacted and sent Unformation about the study if a match was
found with a mother-child pair in the exposed group. Of the 33 children who were originally
Prcnatal Exposurc to Organic Solvcnts 18
tested as matched controls, 5 were omitted for the following reasons: premature birth (n=l),
underdeveloped optic nerve (n=2), behavioural problems (n=l), birth complications (n=l ), for
a final sample of 28 controls with a mean age of 4.9 * 1 .O9 (see Appendix C for a summary
outcome of follow-up).
Solvant-txposed participants were seiected based on the following inciusion cnteria:
only women who were exposed to OS for at least 5 hours per week, and exposure to OS
spanned at l e s t 2 months of pregnancy. Al1 participants abstained fiom alcohol consumption
and recreational dmg use dunng the entire pregnancy, and al1 children were neurologically
normal.
Participants in both groups who met the following cntena were excluded from the
snidy: women exposed to known teratogens other than OS (e.g. lead in paints, carbon
monoxide), women with a psychiatrie illness or endocrine disorder during pregnancy, children
of non-English speaking families, children bom prematurely at less than 36 weeks gestational
age, and children who were believed to be at greater risk of showing abnorrnal visual
development due to family history of heritable retinal disease or congenital colour vision loss.
Procedure
At the time of original contact with the Motherisk Program, a trained counselor
interviewed each woman about her work conditions, use of protective barriers, the distance
from exposure, the number of hours she was exposed to the chemicai per day, and whether she
experienced adverse effects upon exposm. This information was collecteà separately for
diflerent types of OS using a standard questionnaire (see Appendix D). Organic solvents to
Prenatal Exposurc to Organic Solvents t 9
which women were exposed occupationally included aromatic and aliphatic hydrocarbons,
halogenated compounds, alcohols, ketones, glycols and related compounds. Information
about intrauterine exposure to alcohol, tobacco, and other medicinal and recreational dnigs
during pregnancy was also obtained at this time.
Demographic idormation (marital status, education, ethnicity, age, occupation. etc.).
medical history of the mother and child, deveiopmental milestones of the chiid, and duraiion
of breast feeding were obtained using the Case History Report (see Appendix E), which was
compieted by al1 women who participated in the study. Standardized information about
socioeconomic status (SES) fiom ail women enrolled in the study was collected using the
Hollingshead Four Factor Index of Social Status (Hollingshead, 1975). This measure
provides r xighteil average of the mother's and father's occupational and educational level.
Numencal ranges for the social strata of the Hollingshead Four Factor Index are listed in
Appendix F.
In order to control for between-group differences in family functioning, parents were
asked to complete the Family Adaptability and Cohesion Evaluation Scales (FACES III)
(Olson, 1985). FACES UI is a 20-item questionnaire that enables the examiner to classify the
family in terms of (1) family cohesion, ranging fiom disengaged to enmeshed, and (2) family
adaptability, ranging fkom ngid to chaotic (see Appendix G for a sample FACES
questionnaire). This measure is designed to obtain both perceived and ideal family
functioning and to identify the type of family dysfunction. Appendix H lists the range of
scores for categoriang family cohesion and adaptability.
No current information exists on the smetion of organic solvenîs and / or thcir metablites through brcast feeding.
Parents were also asked to complete the Child Behaviour Checklist (CBCL)
(Achenbach, 1991), which is a widely used instrument for providing a standardized, reliable.
and valid description of the child's problem behaviours and social competencies5. Depending
on the age of the child, parents completed either the CBCLU-3 (for children that are less thm
4 years) or the CBCL\4-18 (for children older than 4 years). This questionnaire consists of
100 (for the CBCLV -3) or 1 13 (for the CBCLSJ-18) age-appropriate descriptions that are
rated by the parent on a 3-point scale fkom "not true" to "often hue". The problem behaviour
scale provides indices of total behaviour problems, as well as intemalizing (Le. over-
controlled neurotic-like behaviom) and extemalizing behaviour problems (Le. under-
controlled conduct problem behaviours). The scale also assesses a variety of narrow-band
problerns including aggressive and delinquent acts, withdrawal, somatic cornplaints,
anxiousness or depression, and attention, social, and thought problems. The CBCL is widely
used in developmental research and has excellent psychometric properties (hi& inter-parent
reliability for social problems (I-.77), attention problems (r=.79), deiinquent behaviour
( ~ 7 8 ) . aggressive behaviour (r=.79), extemalizing (r;.80), and overall test-retest reliability
of 0.89).
The administration of the tests to the children was approximately two 1 hour blocks
with a 5 to 10 minute break separating the blocks. Testing was conducted in a quiet room in
the Child Assessment Laboratory of the Psychology Department at The Hospital for Sick
Children. Al1 children were assessed by a ûained examiner working under the supervision of
' Only the CBCLM- 18 has cornpetnice scaies
a registered psychologist. A parent was pennined to observe the experimental setting upon
request of the child. Observers were asked to sit outside the view of the child and to refrain
from communicating with the child. Since the expenmenter was not blind in this snidy, al1
subjective outcome scores (Design Copying and Visuo-rnotor Precision) were scored by
another person who was blind to the child's condition to control for potential expenmental
bias in scoring.
At the conclusion of the study, children received a gi ft (a "Tails" book and
audiocassette produced by the theatre group at The Hospital for Sick Children), and a
certificate of appreciation. The adults were reimbursed for travel expenses (gas, mileage and
parking, or public transit) incurred in coming to The Hospital for Sick Children. A detailed
neuropsychological report and vision test results were provided to the parents wiihin two
months of the assessment. Children who were suspected of having a visual defect were
referred to the ophthalmology c h i c at The Hospital for Sick Children.
*. . ur Vision
Colour vision was assessed by using the Mollon-Rem Minirnalist Test (M-R-M)
(Mollon, Astell & Reffin, 1991; Mollon & Re&, 1994). To evaluate the extent of colow
vision loss, the qualitative details and extent of chromatic deficit were scored on a chart on
which differential chromatic loss in the red @rotan), green (deutan), and blue-yellow (tritan)
range were identified. The Minimalist Test was selected because it has been shown to classify
childm as young as three years with dichromatic colour defects, and unlike many other
colour vision tests, it is sensitive to blue-yellow dyschromatopsia (Leat, Shute, & Westall,
1999). Another important advantage of this test is it can be used successhilly with children
whose visuai acuity is low.
Prenatal to Organic Solvents 22
The M-R-M test consists of thm series of coloured caps coinciding with the protan
(red), deutan (green) and tritan (blue-yellow) confusion axes with a range of six saturations
along each axis. Each chip is assigned a number from 1 to 6 with 1 representing the lest
saturated and 6 the most. The examiner randomly places 5 achromatic chips (varying in
saturation) and 1 chromatic chip on a black table illuminated by standard source C
illumination (Gretaghkcbeth, 617 Little Britain Rd., New Windsor, W. 12523). The test
begins with a saturated orange chip which does not lie on the confusion line. The child was
told that "One of the chips is different. Can you find the chip that is different?". To ensure
compnhension of the task instructions, the examiner did not proceed with testing until the
child succeeded on this pretest. The test continues with the third chip in the protan. deutan or
tritan series. presented one at a time, with random ordering of the three colour series. If the
child accuately identifies the coloured chip, a Iess saturated chip is chosen. This process is
repeated until the child either identifies al1 the chips, for which a score of I is achieved, or
incorrectly identifies the chip for two out of three trials, for which the score is recorded as the
last chip identified correctly. If the child fails to recognize the coloured chip, then the next
chip with higher saturation is introduced. This process is continued until the highest saturated
chip for which the score is recorded as 6. A quantitative evaluation of colour vision outcornes
was carried out by determinhg the score of the least saturated coloured chip identified
correctly. Since acquired dyschromatopsia can be unilateral, the test was performed
monocularly and binocularly. Although there was no time lirnit placed on the subjects, the
test usually took about 6 minutes to complete.
The Cardiff Cards (Adoh, Woodhouse & Oduwaiye, 1992) were used to assess
binocular and monocular acuity. This test uses familiar pictures (e-g. fish, car, dog, duck) of
constant overall size, positioned either at the top or bottom of each card (2 1 x 29.5 cm). The
outline of each figure consists of a white band, flanked on either side by a black band, the
black band being one-haifthe width of the white band. The average luminance of the black
and white bands equals that of the gray background. The angular subtense of the black band
defines the visual resolution in minutes of arc. The card with highest resolution that can be
detected defines visual acuity. Acuity was assessed based on the principle that when the
target figure is presented beyond the observer's resolution limit, it disappears into the gray
background, and nothing is seen. Visual acuity was tested at 1 meter viewing distance and
was scored as the log of the minimum angle of resolution (1ogMA.R) in minutes of arc where O
logMAR is equivalent to 20120 vision and a value mater than O logMAR reflects less than
20120 vision (see Appendix K for a sample of the Cardiff Card scoring sheet).
Clinical tasks were selected fiom validated and standardized test batteries to provide
measures in four domains: verbal ability, attention and executive huictions, visuo-motor
skills, and visuo-spatial ability (Appendix 1 lists the tests in each functional domain for
children aged 3 to 5 years and Appendix J lists the tests in each functional domain for children
aged 5 to 7 years). Criteria for inclusion of a test in the battery include its (1) sensitivity to
measure a particular cognitive huiction, (2) nliability, (3) construct validity, and (4)
practicality and time constraints for use with young chilchen. Furthemore, al1 tests had a
reasonable range of performance outcome measures. The test battery was believed to sample
Prcnatal Exposure to Organic Solvents 24
a variety of different types of cognitive abilities using multiple measures to truly assemble a
picture of impaired versus retained abilities in the face of exposure.
Since visual dysfunction has been reported predominantly in adults exposed to OS. the
primary focus of the neuropsychological testing was visuo-spatial and visuo-motor abilities in
children exposed to OS in utero. Tests of verbal ability were also included in this study in
order to assess whether both groups of children understood task instructions and couid express
themselves equally well. Likewise, tests of attention were included to assess the child's
attentional capacity since deficits in sustaining attention could possibly account for the child's
performance on other neuropsychological measures. While maintaining focus on visual
functions. the wide selection of tasks used in this study has the ability to tap distinct
perceptual and cognitive functions that may possibly be additionally impaired. The order of
tests within blocks (see Table 1 and Table 2) was counterbalanced across participants.
Insert Tables I and 2 about here
Expressive language ability was assessed using selectike language subtests fiom the
Developmental Neuropsychological Assessrnent (NEPSY) (Korkman, 1 W8), as well as the
Expressive One-Word pic^ Vocabulary Test (Revised) (EOWPVT-R, Gardner, 1979). The
NEPSY language subtests included: Body Part Naming, which is an expressive language test
requiring the child to name body parts on a pichm of a child; Speeded Naming, which
quires rapid naming of recuning sizes, colours, and shapes; and Verbal Fluency, which
mesures the child's ability to generate words within a category. The EOWPVT-R requires
naming many pictures of objects and groups of objects.
Receptive language ability was estimated using the NEPSY Phonological Processing
subtest which consists ofsound blending and word completion, the NEPSY Cornprehension
of Instructions subtest, which assesses the child's ability to process and respond to verbal
instructions of increasing syntactic complexity, as well as the Peabody Picture Vocabulary
Test - Third Edition (PPVT-III, Dunn & Dunn, 198 1) which requires the child to point to one
of four pictures named by the examiner. In addition to measunng receptive language ability,
the PPVT-III also served as an estimate of the child's I.Q. since this test is highly predictive of
intelligence.
The Wide Range Assessment of Visual Motor Abilities (WRAVMA) (Adams &
Sheslow, 1995) Pegboard subtest, and the NEPSY Visuo-motor Precision, Design Copying,
and Imitating Hand Positions subtests were used to provide an overall estimate of visual-
motor ability. The WRAVMA Pegboard test was used to assess the child's fine motor skills
by requinng the child to insert as many pegs as possible into a grooved pegboard within 90
seconds. Each hand was tested separately, starting with the child's dominant hand. The
NEPSY Visuo-motor Precision subtest is a paper- and pencil test used to assess fine motor
skills and hand-eye coordination. It requires the child to draw a continuous line on a
cwilinear route as quicldy as possible. The NEPSY Design Copying subtest was used to
measure the chiid's ability to integmte spatial relational information with motor cosrdination.
This test nquires the child to copy NO-dimensional geumetrk designs using paper and pencil.
The presence of hand tremor and a qualitative description of the child's pencil grip was also
recorded. Finally, the NEPSY Imitating Hand Positions subtest was used to assess the child's
ability to reproduce a band position from a mode1 pmented by the examiner.
Visuo-spatial processing was assessed using the WRAVMA Matching, the NEPSY
Block Construction and the NEPSY Arrows subtests. The WRAVMA Matching subtest is a
paper and pend test that assesses various spatial skills such as perspective judgement,
orientation. rotation, and sue discrimination by presenting sets of pictures developmentally
arranged in order of increasing difficulty. The child was asked to indicate which of the four
options 'goes best' with the item standard. WRAVMA validity studies have shown that the
performance on the Matching subtest is more highly correlated with traditional tasks of spatial
skills (e.g. WISC-III Block Design, r=.61) than with verbal tasks (e.g. WISC-III
Comprehension, ~ 3 6 ) (Adams & Sheslow, 1995). The NEPSY Block Construction subtest
was administered to assess the child's ability to reproduce, h m models and pictures, block
constructions in three dimensions in a specified time limit. The child's score was deterrnined
by the number of correct constructions made. The NEPSY Arrows is a non-motor subtest
used to assess the child's ability to judge the direction, angularity, and orientation of lines.
The child was required to choose two m w s that point to the center ofa target fiom an array
of arrows.
Attention
Attention was assessed using the NEPSY Tower, Visual Attention, and Statue
subtests, as well as a vigilance Continuous Performance Test (CPT). The NEPSY Tower
subtest was used to assess the executive functions of planning, monitoring, self-regulation,
and problem-solving. It required the child to move three coloured balls to target positions as
quickly as possible according to a set of d e s . The Visual Attention subtest measured speed
and accuracy in scanning a linear or random array to locate a target picture which become
increasingly more complex with age. The NEPSY Statue subtest was used to assess the
child's inhibition and motor persistence. The task required the child to stand still in a set
position over a 75-second period while inhibiting responses (e.g. eye opening, body
movement, vocalization) to distracters. Lastly, a visuai CPT was used to measure the child's
vigilance (i.e. the maintenance of attention for infiequent but critical events over sustained
periods of time) which is thought to be closely regulated by arousal. The level of vigilance
was measund as the child's overall ability to identib targets correctly over the entire length
of the task. For children aged 3 to 6 years, the "Birdie in the Tree" CPT was used. This test
was a simple signal detection paradigrn where the children waited for a specified target item
to appear on a computer screen. The paradigm was explained in the context of a story about a
"silly tree" that had a nurnber of items in it that did not belong in the tree (cg. sailboat, fish,
train, telephone, etc.). The child's task was to press a telegraph key whenever a bird appeared
in the tree and resist pressing the key when other objects appeared. Children older than 6
years were tested with the C o ~ e n CPT (Corners, 1992), which required them to press a
teiegraph key each time a letter appeared on the screen and resist pressing the key when an
'X' appeared. Erron of omission and commission and mean reaction t h e were scored for
each CPT. Various modifications of CPT-type tasks have been used as laboratory measures
of attentionai problems, and false-alarm errors have been reported at increased levels among
hyperactive children and leaming-disabled, nonhyperactive childm (cited in Kopera-Frye,
Camichael Olsen & Streissguth, 1997). Furthetmore, performance on CPTs is correlated
with ratings of child impulsivity, organization, and endurance during the laboratory setting.
Women in the exposed group were dichotomized as having either a high or low
exposure to OS. Determination oflevel of exposure (high or low) was based on the woman's
exposure intensity (assessed using the weighted algonthm). Since the distribution of exposure
intensity was normal, exposure estimates greater than the median were categonzed as "high"
exposure, and scores less than and equal to the median were categorized as "low" exposure.
Women in the contrd group were entered into the analyses as having "no" exposure.
Statistical analyses were performed using version 6.12 of the Statistical Analysis
System package (SAS). Demographic data were analyzed with pararnetric and nonparametnc
tests depending on the nature of the measurement and the distribution. Discrete variables,
such as smoking and birth order, were analyzed with the chi-square test. Continuous
variables, including age, number of years of education and developmental milestones, were
assesseci with t-tests.
Control variables, including potential confounders and matching variables, were
analyzed using Pearson comlation coe~cients. The following variables were added as
covariates: age ofchild, gender of child, gestational age, age of rnother, yean of education,
socioeconomic status, smoking habits during pregnancy, and length of breast feeding. These
variables were prescreeneû based on the method describeci by Jacobson and Jacobson (1996)
to determine which to include in the multivariate anaiyses. This prescreening excludes
variables that are unrelated to the outcome so that the e m r tem is not reduced, thereby
improving the chances of detecting real toxic effects. Control variables were selected by
exarnining their univariate relations with each outcome. Al1 control variables that were at
least weakly related to the outcome being evaluated (at pc0.10) were considered as potentiai
confounders and were included as covariates in the analyses (see below). This pc0.10
criterion is conservative in this context because it includes even weak potential confounders.
Quantitative evaluation of the Minirnalist Test was done by caiculating the results of
both eyes (binocular score) and the mean results of the siagle eyes (monocular score) for each
child. The Wilcoxon-Mann- Whitney test (two-sided) was used to evaluate di fferences in
binocular and monocular chromatic discrimination between groups. LogMAR scores of the
visual acuity test were also analyzed using Wilcoxon-Mann-Whitney test. The relationship
between level of exposure and visual functioning was studied using a logistic regression
mode1 to determine whether there is a dose-level effect of the exposure.
To test the hypothesis of an association between prenatal solvent exposure and
performance on cognitive tests, exposed and unexposed groups were compared using unpaired
two-tailed t-tests (crude analysis). If an association was suggested by this analysis, multiple
regressions or analyses of covariance (ANCOVA) were used to assess the effects of solvent
exposure for each univariate effect. Covariates were determined separately for each
dependent variable based on a correlational analysis (see above). Al1 test results were
converted to z-scores on the basis of appropriate age noms. so that cornparisons between tests
could be made. Overall domain effects were analyzed by taking the average z-score for eac h
observation in each domain A toxic effect was inferred oniy if the relation between exposure
and outcome was significant at pcO.05 after controllhg for the confounding variables.
Prcnatal Exposurc to Organic Solvents 30
The collapsing of subtests within domains is bas& on considerations of test
inteicorrelations, and the nature of the tasks. The organization of the scores into domains
facilitates evahation of children's problems at relatively differentiated and more global levels.
This approach enables one to organize information in a systematic and useful way. It is then
possible to focus attention on syndromes of items found to CO-occur rather than dealing with
separate pmblems one-by-one.
Multiple regression analyses were perfonned using z-scores on each subtest as the
dependent variable and length of exposure. duration, symptomology, ventilation, and level of
exposure (hi&, low, or none) as the predictor (independent) variables. For each outcome
variable analyzed, the parameter(s) that accounted for the most amount of variance in the
mode1 was reporteci. Parameters which were predictive of outcome were interpreted to
indicate which dimensions of exposure (Le. length, duration, symptomoIogy. etc.) are most
strongly associated with the outcome measure. For al1 statistical analyses. the alpha level was
set at 0.05.
Prenatal Exposurc to Organic Solvents 3 1
Results
Results show that 70% of women who were successfully contacted and identified with
solvent exposure between 1992 and 1996 agreed to participate in the study compared to 76%
of the women in the control group. Appendix K provides information comparing the groups
on participation rates and on meeting the inclusion and exclusion criteria. Based on telephone
interviews, more pregnancies in the exposed goup resulted in miscarriage (6%) or
prematurity (4.5%) compared to the control group (2.5% and 2.5% respectively).
Table 3 shows the occupations and estimated solvent-exposures of the women who
were in the original cohort and of those whose children were evaluated in the present study.
The most cornmon occupations were iaboratory technicians, factory worken, and graphic
designers in boih the original and study cohort. in the original cohort, most women worked in
a factory (23%) followed by a laboratory (20%), whereas most women in the study group
worked in a laboratory (28%) followed by a factory (16%). However, the di fferences in type
of occupation between groups was not significant @=0.09). Chi-squared analysis showed that
more women in the original cohon were exposed to aliphatic hydrocarbons compared to the
women in the study cohort who were most frequently exposed to halogenated solvents
(p<O.OS). Because most of the women had exposures to more than one type of solvent,
analysis by type of solvent was not possible.
insert Table 3 about here
For both exposed and control groups, demographic and pregnancy-related information
about the women and their children is shown in Table 4. Six variables were used for
matching: gender and age of child, ethnicity, matemal years of education, socioecononomic
and marital status. To assess the effectiveness of matching, two-tailed t-tests or chi-squares
were performed on each matching variable. The mean Hollingshead score in the women in
the exposed group (M=43.28, m40 .73) was almost identical to the control women
(M=45.48, ==6.18), in the same socioeconomic stratum (medium business, minor
professional, technical), while the difference between groups was not significant, 1 (59)~-0.96.
9~0.32. Similarly, the groups did not differ in number of years of matemal education (1
(59)=0.78, p=0.44). Family cohesion, as measured by the FACES III, was rated as
"connecteci" for both the exposed (M42.60, ==3.74) and the control group (M=42.57.
==3.20) and no significant difference was found between groups ( ~ ( 5 8 ) = 0.049, p=0.975).
Family adaptability ratings, on the other hand, were slightly more toward the "stmctured"
range in the exposed group (M=24.47, ==7.39), compared to the control group who were
slightly more toward the "flexible" range (M=25.78, ==4.34). However, the difference
between groups in family adaptability was not significantly different (1 (58) = -0.821,
0=O.415).
insert Table 4 about here
Children in the control group were similar to children in the exposed group in almost
al1 demographic aspecis, except f ~ i more of their rnothers were older (L(59)=-2.44, H.03).
An approximate qua1 proportion of females and males were examined in each group. Groups
did not differ significantly on the number of days spent in the hospital after birth (i (56) -0.92,
p=û.36), gestational week at delivery (l(5 8)=O.M, g=û.73), child' s age at testing (1 (Sg)=O -92,
p=0.36), birth order (x2=( 1, N=61)=0.99, p=0.3 l), and matemal smoking during pregnancy
(X2=(1, N=6 1)=1.47,~=0.23).
The children's developmental milestones (as reported by the mother) are summarized
in Table 5. Results show that children of solvent-exposed women were not reportedly delayed
in walking (f ( 5 5 ) = -0.63, p=0.54), speaking first words (1 (46) = -1.74, p=0.10), or speaking
first sentences O (37) = -0.60, H.55). However, significant differences were found between
groups on age to crawl, f (40) = -2.47, p=0.02, and nui, 1 (42) = 3.16, pe0.01. Solvent-
exposed children were reported to crawl one month earlier (M=7.33, == 1.55) than children
in the control group (M98.77, ==2.60), but were later to run (M=19.83, SD=6.77) than non-
exposed children (M43.3 1, SD41.14). With respect to measures of growth, children of
solvent-exposed wornen were no more delayed than children of non-exposed women4.
Weight, height and head circumference measurements are summarized in Table 6.
Insert Tables 5 and 6 about here
Mother's ratings of their child's behaviour are reported in Table 7. With regard to behaviour
problems, no significant mean T-score differences were found between groups on any of the
CBCL narrow band scales [sleep pmblems (1 (14)==-0.08, fl.93). withdrawal behaviour (1
(58)=O. 17, p=0.36), sornatic cornplaints 0 (58)=0.37, p=0.07), anxiety (g (42)=0.97, p4.8 l),
social problems a (42)=0.43, p=0.54). thought problems (1 (42p1.80, ~=0.08), attention
problems (42)=-0.68, g=0.50), delinquenc y O (42)==.73, p=0.47), destructiveness (1
Prenatal Exposure to Organic Solvents 34
(14)=1.10, @.29), or aggressiveness (J (58)4.82, p=0.93)]. The groups also did not differ
on total problems [total problems (1 (S8)=1.85, p=0.07), intemalizing behaviours (1 (58)=1.79.
~=0.08), and extemalizing behaviours (58)=0.95, p4.35). The mean T-scores on the
CBCL were within a standard deviation of those expected for children in their age-group. It
should be noted, however, that there was a trend towards higher mean T-scores in the exposed
youp for all behavioural measures except for sleep and attention probiems. The higher scores
in the exposed group on the total problems and intemalizing behaviours likely reflects an
(non-significant) increased incidence of thought problems and somatic complaints.
Insert Table 7 about here
When the data were analyzed using a chi-square analysis, significantly more children in the
exposed group received a rating by their mother that was greater than the cutoff for borderline
behaviour (Le. T-score greater than 67) than in the control group (X' (1, N=6 1)=4.75, p=.03).
Figure 1 sumrnarizes the proportion of children per group who received a rating greater than
the cuto ff for borderline behaviour.
insert Figure 1 about here
The Minimdist Test scores were analyzed using the Mann-Whitney U-test because the
' Measurcs of bu<h weight were not comistentîy obtaincd for each chiid at the iime of follow-up and the~fore, are not rcported.
Prcnatal Exposure to Organic Solvents 35
data were skewed and no transformations to a normal distribution were possible. Also,
nonpararnetric distribution fkee tests should be used when analyzing data fiom an ordinal scale
such as the Minimalist Test. Results were reported using the KrusKal-Wallis chi-square
approximation5. Results showed that the both binocular and monocular colour vision scores
were significantly higher in the exposed group for the protan (binocular: H4.52, 1, ~~0.03;
monocular: fi=l l . I l , 1, p<0.001) and tritan (binocular: U=9.34, 1, p<0.003; monocular:
B=10.72, 1, p<0.002), but not for the deutan (binocular: m . 1 4 , 1, p=0.05; monocular:
H=3.61, 1, p=0.07) colour conhsion lines. Figure 2 shows the mean binocular and monocular
insert Figures 2 and 3 about here
scores of the exposed and control groups for each colour confusion line. Tables 8 and 9 show
the fiequency of scores on the Minimalist test for exposed and control groups for binocular
and averaged monocular testing respectively. For a graphical representation, see Figure 3 for
Gequency of binocular scores for exposed and control groups on the Minimalist Test. In the
total sample, 2 out of 15 boys (1 3.3%) and 1 out of 17 girls (5.9%) in the exposed group were
classified as having a clinical red-green colour deficiency according to the limits of the
Minimalist Test compared to zero colour deficient children in the control group.
hert Tables 8 and 9 about here
Amoog the 33 childm in the cxpoecd group, 1 d e was excludcd because of congcnital colour blindness and 4 children r t k d to Wear the patch for testhg monocular colour vision, Among tbc 28 childrcn in the control group, 1 child fcll askcp for al1 visual tests and 1 child rehistd ta wciu the patch for testing rnonocular colour vision.
Prenatal Exposure to Organic Solvcnts 36
The relative risk of solvent-exposed males with rd-green color defects (1 3.3%)
compared with the incidence of males in the general population with such defects (8%) is not
significant (p4.50). However, it should be noted that the estimated 8% of males with red-
green color vision loss in the general population includes those with hereditary color vision
defects. It would be expected, therefore, that the incidence of males with red-green defects
would be less than 8% as we excluded those with known hereditary color vision defects.
Assuming a conservative estimate of 2% of males with a color vision defect not attnbutable to
a hereditary effect, the relative risk of color vision loss in the solvent-exposed males is 0.234
(95% CI: 0.065 - 0.842, pe0.03).
Logistic regression was performed to determine whether the presence of a colour
defect versus no colour defect could be predicted fkom exposure variables. B a d on the
explanatory variables included in our model, we could not predict the odds and probabilities
of having a colour discrimination defect. However, results of an ANCOVA showed that level
of exposure (hi*, low, or none) had a significant effect on the value of the log transformed
tritan score, E (2,55)=4.67, p4.01. ANCOVAs for the deutan and protan data showed weak
statistical evidence that level of exposure is nlated to colour discrimination.
Since no children in the study group wore glasses, al1 acuity scores represent
uncomcted vision. The Wilcoxon rank-sum test indicated that solvent-exposed children had
poorer binocular (M=0.07, m4.08) and monocular (M-0.10, ==O. 10) visual acuity than
Prenatal Exposure to Organic Solvents 37
children in the control group (binocular: M4.02, ==O.OS; monocular: M=0.05, m=0.06)".
Figure 4 shows the binocular and monocular mean visual acuity logMAR scores for the
exposed and control gmups. Although the differences are signi ficant (binocular: H=8.20. 1,
p<0.004, monocular: H4.47, 1, ~<0.034), acuity scores in the exposed group are within the
normal age-range and are not clinically significant.
Insert Figure 4 about here
Logistic regression was perforrned to determine whether visual acuity could be
predicted fiom exposure variables. Visual acuity of O logMAR (equivalent to 20120 vision)
versus acuity greater than O logMAR (Le. poorer acuity) were used as outcome variables with
level and length of exposure as predictor variables. Based on the explanatory variables
included in this model, we could not predict the odds and probabilities of having 20/20 visual
acuity.
Receptive and expressive language domain scores are summarized in Table 10.
Results showed a significant domain effect between groups on expressive language ability
0(59)=3.109, g=0.003), but not on receptive language ability ($(59)=1.632, p=O.108).
' Among tht 33 childrcn in the exposcd group, I maic was cxcludcd for a family history of visual defects and data fiom 2 childrcn were not included in the analysis because the confidence of the measurcmcnt was poor due to the childrcn jumping out of thcir scat to sec the card Mer . Another child in the exposcd group was excluded fiom the monocular visuai acuity analysis because he refiised ta Wear the eye patch. Arnong the 28 childrtn in the controt group, 2 childrcn were not included in îhe b i n d a r visual acuity analysis because the confidence of measwment was poor and another 2 were excluded fiom the monocular amlysis because they refuscd to Wear the patch.
Prcnatal Exposure to Organic Solvents 38
Insert Table 10 about here
Univariate results on tasks of expressive language are reported in Table 1 1. When
tests were anaiyzed individually using ANCOVAs, results showed a significant difference
between the exposed and control group on the EOWPVT-R with children in the exposed
group doing worse with adjustment for potential confounding factors, matemal age and
education, (E (1, 58) =5.83, pc0.02). Performance on al1 other expressive language subtests
did not differ significantly between groups [(Body Part Naming, (1 (35)=-1.66, p=0.08);
Speeded Naming, (1 (1 8)= 1.97, p-0.07); Verbal Fluency, (1 ( 5 6 ) ~ 1.26, p=0.2 1 )]. It should
be noted, however, that a trend in the results showed that chilâren in the exposed group
perfonned more poorly on most of the other tasks of expressive language compared to the
control group.
Insert Tabie 1 1 about here
On tasks of receptive language, no significant group differences were found [(PPVT-[II,
(1 ( 5 9 ) ~ 1.28, ~=0.20); Comprehension of Instructions, (1 (58)=0.77,9=0.44); P honological
hcessing, O (36)=-1.53, p=û. 1 S)]. Similar to the performance on tasks of expressive
language, a trend in the results showed that solvent-exposed children performed more poorly
on tasks of receptive language compared to the children in the control group. When the data
were analyzed by level of exposure (high, low, none) as the independent variable, results
reveaied a tendency for scores on the PPVT-III to get wone as exposure level increased,
Prcnatal Exposure to Organic Solvents 39
adjusting for matemal education, E(2,57)=3.9 1, p=O.O3. Furthemore, mean scores for high,
low and no exposure differed significantly on Phonological Processing when age of child,
matemal education, and gestational age were used as covariates, E (2,33)= 1 7.68, p=0.02. No
dose-response relationship was found on the Comprehension of Instructions subtest.
Multiple regmsion analyses showed that some of the exposure variables were good
predictors of ianguage outcome as summarized in Table 12. Exposure variables were
signi ficantly related to Phonological Processing, Comprehension of Instructions, EO WPVT-R
and PPVT-III, but not on Body Part Naming, Speeded Naming and Verbal Fluency subtests.
For Phonological Processing, length of exposure (lu trimester versus full term) appeared to be
the best predictor of performance on with 27.82% of the variance accounted for by this
variable alone. The addition of the estimated exposure index into the model increased the
variance explained to 0.56 which is quite high. This hi& association between length of
exposure and Phonological Processing, E (2, 17)=9.75, p=0.002, is most suggestive of a
temporal-response relationship out of d l the outcome measures. For Comprehension of
Instructions, length of exposure, duration of exposure, and symptomology are al1 strong
predictors E (3,28)=6.40, p=0.002. On the PPVT-III, duation, ventilation and exposure
index were found to be the best predictors of outcome, E (3,29) = 6.48, g.0.002. Finally,
poorer performance on the EOWPVTR was associated with increased number of houn
worked per week, E (1,29)=5.33,@.03. The direction of the relationship was as predicted,
with poorer performance associated with higher exposure iniensity, longer length of exposure,
and increased fiequency of reported adverse effects. The exposure effects were described by a
hear model, meaning that prenatal solvent effects were estimated to Uicrease linearly.
Prcnatal Exposurc to Organic Solvents 40
insert Table 12 about here
Analysis of the visuo-spatial data revealed the domain effect was not significant between
groups. t(Sg)=-l.73. p=0.09. However. children in the exposed group showed a tendency to
perform more poorly on tasks of visuo-spatial ability than controls. Table 13 shows the mean
z-scores for the two groups. On individual tasks, significant between-group differences were
found on Block Constmction. E (3, 57)=3.36, p=0.025, adjusted for age of child and matemal
age. No effects were found on the Matching, 1 (58)=0.53,~=0.60 or Arrows, 1 (22)=-1 .OS.
~30.30 subtests. Multiple regression did not reveal any significant relationships between
erposure vari-ables and outcome measures.
Insert Table 13 about here
Based on a factor analysis of the visuo-motor data, results were organized using 2
factors: fine-motor and graphomotor ability. On fine-motor ability, no overall domain effect
was founâ, t(59)==-0.06, p=0.95. On graphomotor ability, however, an overall domain e ffect
was found, t(59)=2.44, p4.02, showing pwrer performance in the exposed group. Table 14
shows the mean z-scores on tasb of fine-motor and graphomotor ability for exposed and
control groups. No significant between-group diffemces were found on univariate analyses
of fine-motor ability [Pegboard Test (dominant hand), (1 (59)=0.00,@.99); Hand Positions,
Rcnatal Exposure to Organic Solvents 4 1
(1 (53) =0.06, ~=0.95)]. On tasks of graphomotor ability, M O V A (adjusted for gender of
child, age of child, and matemal age) revealed significant between-group effects on the
Design Copying subtest, E (4,60)=3.85, g=0.01, and Visuo-motor Precision, E (2,60)=3.98,
g=0.024 (adj usted for gender of child).
Insert Table 14 about here
Multiple regression analyses, as summarized in Table 15, revealed a tendency for
performance on both tasks of graphomotor ability, Design Copying and Visuo-motor
Precision, to get wone as exposure level increased. On both graphomotor outcorne measures,
the effects are described by a linear rnodel, with exposure variable values linearly associated
with deficits in ability. Poorer performance on the Design Copying was associated with
higher exposure intensity and fewer ventilation measures, E (2,29)=8.37,0=0.002, while
deficits on the Visuomotor Precision subtest were associated with increased length of
exposure and higher number of reported adverse effects, E (2,30)=4.74, p=0.02.
Insert Tabie 15 about here
Attention
Overall, the gmups did not differ in the attention domain, f (58)=O.CS, g=0.94.
Univariate analyses also did not reveai any significant differences between gmups [Statue, (1
(55) ~ 1 . 2 2 , ~30.23); Visuai Attention, @ (53) =1.50, fl.14); Tower, (t (22) 4.67,
Prcnatal E q o m to Organic Solvents 42
g=0.5 l)]. Mean z-scores on taslrs of attention are provided in Table 16'.
lnsert Table 1 6 about here
' The d t s of tûe "Budie in the tm" CPT arc not pesented as part of this paper bccaux the scoring for this meamire has yct to be established- Conner's CPT rmilts are not reportcd as part of this paper because the numbcr of children complcting this task was too d. Rcsults of these îasks will bc part of a subsequent publication.
Prenatal Exposurc to Organic Solvents 43
Discussion
The intent of this study was to investigate the effects of maternai occupational
exposure to OS on visual and cognitive development in the offspring. The specific locus of
the study on visual huictioning was prompted by past studies on animals and adults showing
that the visual system may be especially vulnerable to solvent exposure. Based on ihis
vulnerability, we hypothesized that prenatal exposure to OS wouid disnipt visual development
and result in long-terni perturbations in colour vision and visual acuity. Given the assurnption
of an underlying dysfunction of the visual system, chiken exposed to OS in urero were
expected to show deficits on tasks of visuo-spatial and visuo-motor ability. Prenatal exposure
to OS was also predicted to disnipt language and attention because exposure during a cntical
period of brain development may affect emerging cognitive huictions. Finally, it was
hypothesized that higher doses and increased length of exposure to OS would be associated
with more pronounced deficits in visual and cognitive functioning.
The results of the present study provide support for the first hypothesis that matemal
occupational exposure to OS during pregnancy is associated with adverse effects on their
chilci's subsequent colour vision and visual acuity. The colour vision deficits that were found
among the solvent-exposed group were mainly of the tritan (blue-yellow) category suggesting
evidence of an acquired dyschromatopsia. Interestingly, clinical red-green colour vision
deficits were identified in 3 children in the exposed group compared to O in the referent group.
On tasks of cognitive hctioning, mild deficiencies were detected in expressive language,
block construction, and graphomotor ability. The observed deficits on block construction and
graphomotor ability provide tentative evidence of an impairnent to the visual system that may
subserve these abilities. At the present the , however, it is t w early to interpret where in the
Prenatal Exposure to Organic Solvents 44
brain neurobiological changes occurred. The approach used in this study was largely
clinically based using standard tests of visual and cognitive hctioning. Further research
using neurochemical, anatomical and neurophysiological methods is needed to guide this
work and find information about the effects of prenatal solvent exposure on brain
development .
The central finding of this sîudy is the increased number of colour vision deficiencies
in children exposed to OS Ni utero. Of particular interest is the greater incidence of tritan
(blue-yellow) discrimination deficiencies in the solvent-exposed group than the control group.
This discovery presents preliminary evidence of a solvent-induced neural alteration in prenatal
visual development. The possibility that the deficit was inherited is unlikely since defects in
the tritan pigment are not sex-linked and very few people have an inhented blue-yellow
defect, occumng equally in both sexes in about 0.002 to 0.007 percent of the population
(Pokomy, Smith & Vemest, 1979). Furthemore, past studies have shown that blue-sensitive
cones are generally more susceptible to toxic substances than red- and green-sensitive cones
(Mergler, Bélanger, Grosbois & Vac hon, 1 988). Given the rarity of tritan de fi ciencies in the
general population, our finding provides strong support that prenatal exposure to OS may be
associated with an acquired colour vision deficiency. This observation is consistent with the
acquired blue-yellow colour vision loss reported in adults exposed occupationally to OS.
The pmsent findings are also of clinical importance with respect to rd-green clinical
colour discrimination deficiencies. Even after excluding al1 children with a family history of
colour vision defeets, we identified 2 out of 15 boys (1 3.3%) and 1 out of 17 (5.9%) girls in
the exposed group with a clinical rd-green colour deficiency compareci to O children in the
Prenatal Exposure to Orgaaic Solvents 45
control group. This is a very high prevalence when compared to the general population where
the incidence of red-green colour blindness is 8% for males and 0.4% for females (Pokomy et
al., 1979). The incidence of colour blindness in the general population would be even less
when cases with a family history of colour vision defects are excluded as in our sample.
Although the red (protan) and green (deutan) type of congenital colour vision deficiencies
could have been transmitted by a recessive X-linked mode of inheritance by the mother, the
probability of this happening is equally likely to occur in both groups. These findings
therefore suggest that prenatai solvent exposure may be linked to an increased incidence of
acquircd colour vision defects.
Poorer chromatic discrimination among solvent-exposed children was found despite
precautions that should have minimized group differences. Specifically, al1 children who
were believed to be at greater risk of showing abnomal visual development due to a farnily
history of heritable retinal disease or congenital colour vision loss were omitted from the
analyses. Ail children were tested by the sarne penon to reduce any variation in test
administration. To ensure adequate visual acuity, al1 chilâren were prescreened for normal
acuity for their age (see Appendix 1 for the logMAR chart used to determine normal acuity).
The subject groups were well matched on age and gender, and no significant differences were
found in performance by age or gender. Finally, it is unlikely that the deficits in chromatic
discrimination were due to cognitive diffaences between groups because minimal cognitive
and attentional demands were required by the Minimalist Test. To ensure adequate
comprehension of the test instructions, the examiner did not begin testing until the child
succeeded on the pretest.
Prenatal Exposure to Organic Solvents 46
in children exposed in utero to OS, we do not yet know where dong the complex
network of interconnecting neurons of the pnmary visual pathway the impairment resides.
Because similar effects on colour vision have been reported in adults exposed to OS. it is
suggested that similar pathways or systems may also be disrupted by prenatal solvent
exposure in the fetus during visual development. According to Koilner's nile, most blue-
yellow defects appear in retinal disease and are believed to occur at an eariy stage in visual
dysfunction of optic neuropathy; red-green defects, on the other hand, mostly appear in optic
nente disease and are associated with more severe optic neuropathy (Hart. 1987). Since an
increased incidence of chromatic discrimination impairments were found on al1 colour
confusion lines among children exposed to OS in utero, our findings may reflect changes to
both retinal layers and optic nerve.
Some hypotheses can be made on the specific mechanisms involved in the neuro-
ophthalmotoxicity ofprenatal exposure to OS based on research findings of past studies.
Blain et al. (1994) perfomed electroretinographic measurements on rabbits chronically
exposed to tricholoroethylene (TRI) and found that its metabolite trichloroethanol (TCE)
modifies retinal physiology. They suggested that the retinal changes caused by chronic
exposw to TRI increases the penneability of Miiller cells to extracellular potassium,
enhances the axonal transport, and potentiates the retinal doparninergic system. It is possible
that prenatal exposure to OS also interferes with the retinal dopaminergic system resulting in
alterations in the neural Functioning of retinal cells and / or optic pathways. Although other
studies support the idea that alterations to dopamine levels in eariy life can impair visual
bctioning (e.g. Diamond & Herzberg, 1996), ihis hypothesis should bc m e r explored.
Prenatal Exposure to Organic Solvents 47
e of a Dose- or T
The fhdings showed that colour discrimination capacity for the blue-yellow range was
worse for the high exposure group compared to the low and no exposure groups. This dose-
response relationship led us to examine whether children with the most severe colour vision
defects (Le. complex dyschromatopsia in both the Mue-yellow and the red-green range) were
associated with high levels of exposure. interestingly, the results did not show a dose- or
temporal-response relationship between exposure level and seventy of colour discrimination
impairment. Only one of the three mothers of children identified as having a clinical red-
green defect was exposed to a hi& level of OS (refer to Appendix J, Case History 1 for a
description of the mother's exposure history), whereas the other two were categorized as
having low exposure to OS during pregnancy (refer to Case History 2 and 3, Appendix J).
This discrepancy suggests that clinical colour vision loss may occur even when the mother's
exposure is low and asymptomatic dunng pregnancy. It should also be noted that the
observed cases with clinical colour vision impairment were not associated with a speci fic
occupationa or type of solvent.
As predicted, the solvent-exposed group showed a trend for poorer performance on
most subtests compared to the reference group, and chilchen in the low exposure p u p did
somewhat better than children in the high exposure group. Significant differences were
detected on selective tasks of expressive language, visuo-spatial and graphomotor ability. The
' Mn. X (Case History 1) hPd the highcst exposuce. She worked in a printing factory and was prllannly exposed to mcthyl cthyl kctonc (MEIC). MIS. Y (Case History 2) worked as a lab technician in a paint factory and was exposed to ammatic hydroc;ins, alcohols, ME.K and complex solvcnts. Mn. 2 (Case History 3) worked as a chemist and was exposcd to halogenated compounds, alcohols and to a lcsscr extcnt, aromatic hydrocarbons.
Prtnatal Exposurt to Organic SoIvents 48
reason that most tests did not attain statistical significance may be because of the srnall sarnple
size a d o r because the effects 010s are typically subtle raising questions of adequate power
in this study. Our findings are sirnilar to those of other studies on workers occupationally
exposed to OS in that differences are relatively mild and cover a variety of mental fictions.
Even though the cognitive deficits fond in this study were subtle, they are relevant to the
assessrnent of whether neurodevelopmental deficits occur, and the evaluation of the relation
between dose and response. However, in evaluating the results, the limitations of the study
should be considered.
. . cts on A b u
An overall domain effect of prenatal exposure to OS was observed on expressive
language but not receptive language. Since early developmental characteristics are suggested
to be early indicators of later functional development (Kenemaekers et al., 1997), we
predicted that the observed deficit in expressive language would correlate with a delay in age
to speak first words or use first sentences. However, this was not the case; the solvent-
exposed children acquired use of first words and sentences at the sarne age as the reference
group. The discrepancy between the observed deficit in expressive language but not in
language milestones can be explained by one of Kennard's (1 940) early observations: "that
certain behavioral impainnents do not occur immediately after early brain damage, but
emerge only later in development, at a t h e when the relevant behavior would normally
appear" (cited in Dennis, 1988, p.97). What Kennard proposed, in essence, was that a lesion
in early development may produce relatively few irnmediate problems, but that durhg later
development, the lesion may cause the young brain damaged organism to "fail to acquire"
(Kennard, 1940, p.388, cited in Dennis, 1988) a skill.
Prenatal Exposure to Organic Solvents 49
Convergent evidence of a targeted effect of prenatal exposure to OS was observed on
tasks of graphomotor ability. Results showed that solvent-exposed children perfonned
significantly worse on the Design Copying and Visuo-motor Precision subtests even d e r
statistically adjusting for a variety of potential confounding variables. Furthemore. a dose-
response cffect refiected poorer graphomotor ability with increasing exposure level. One
proposed reason for this specific impairment may be related to an underlying dysfunction of
the visual system. Ifearly exposure to OS results in structural malformations of the visual
system, this may lead to less efficient integration of visual information with higher-order
processes. Further studies should explore the hypothesis that early damage to some portion of
the pnmary visual sysiem may contribute to reduced input to the undarnaged area.
Evidence of a Ternooral-Re- of Pr- tto Or& S o l v w
It is well known that "susceptibility to teratogenic agents varies with the
developmental stage at the time of exposure" (Wilson, 1977, p.50). This pnnciple of critical
periods in behavioural teratology divides susceptibility to prenatal damage into periods
depending on their degree of vulnerability. Generally, these periods are termed:
preimplantation, organogenesis, histogenesis, and functional organization. Our attempt to
explain the variation in cognitive outcome as a huiction of critical periods was for the most
part not very fruitful. It appears that exposure does not have to span the entire pregnancy for
suhtle defi&nc#9 to be detected in the offspring, suggesting that maximal sensitivity to OS
occurs during kt-trimester organogenesis in humans. increased teratogenic vulnerabili ty of
the brain during organogenesis has also been shown with other teratogens including
antimitotic agents, vitamin A, neuroleptics, anticonvulsaats, akohol, opiates and irradiation
Prcnatal Exposwe to Organic Solvcnts 50
(Shepard, Fantel & Mirkes, 1993; Vorhees, 1986).
For the most part, the results of the current study support the concept suggested by
Wilson (1977) that the susceptibility of neurotoxic insult generally dirninishes with advancing
development. interestingly, the Phonological Processing subtest was the only task that
showed a strong temporal relationship between outcorne and length of exposure. This task.
which consists of sound blending and word completion, is unique because it was the oniy one
that depended highly on hearing ability. The heightened sensitivity on the Phonological
Processing subtest rnay pnsent evidence of a longer period of increased vulnerability of the
developing auditory system. Although the auditory system is believed to mature somewhat
earlier than the visual system, there are data to suggest that the developing auditory system is
still subject to injury even in the perinatal period (reviewed in Rodier, 1994). The auditory
system's critical period of development, therefore, may span a longer period compared to the
visual system. Moreover, evidence that OS can induce hearing losses cornes Frorn past studies
in rats (Nylén, Hagman & Johnson, 1995; Loquet, Campo & Lataye, 1999). Based on
electrophysiological and histological data, Loquet et al. showed that styrene and toluene can
cause auditory threshold shiAs in mid (16 kHz) and mid-low (4 Hz) Frequency regions, while
high styrene concentrations are capable of causing fiequency-independent hearing losses.
Although the evidence of a hearing impairment associated with Full tenn exposure to OS is
preliminary, hture studies should include hearing and auditory processing tests as part of a
hi11 clinicd examination of neurotoxicity.
It is largely unknown why fetal teratogenic effects are not always seen in children after
apparently similar prenatal exposure. Our hdings revealed high variability in the magnitude
Prenatal Exposure to Organic Solvents 5 1
of effects in children, even though their mothers were exposed to the sarne OS under similar
conditions. This variability most likely reflects a combination of factors, such as differences
in metabolic rate, timing of exposure during pregnancy, or interactions with other variables
known to affect exposure such as smoking and alcohol.
Although the dose and timing of prenatal exposure explains some of this variability,
inter-individual variability as to when the effects may manifest is another possibility .
Children with similar exposures may show different effects due to an altered dynarnic
plasticity in the brain. This brings up an interesting philosophical question of whether a more
legitimate route to understanding the cognitive effects of prenatal solvent exposure lies in
studies that do not involve averaging across subjects. Mer all. it was this motivation for the
case study method that gave rise to the prominent cognitive neuropsychology research of
language that began about 25 yean ago (Goodglass & Wingfield, 1998).
Before the deficits can be attributed to prenatal solvent exposure, some
methodological considerations need to be discussed. Fintly, valid cause and effect inference
can not be drawn based on this type of research design because random assignrnent and
expenmental control over extraneous influences are not possible. The matched cohon design
is limited because it can not tell the tnie impact of the matched variable nor does it assure that
cases and controls were comparable in al1 respects. Although it wouid be ideal to match
children and women on every possible variable that could afFect performance, this is not
possible in research with humans. Thus, control For confounding is a primary concem for this
type of study and alternative explanatioas for obsened effects must be carefully evaluated.
Prenatal Exposwe to Organic Solvenis 52
Secondly, the study of behavioural teratology is complicated by the difficulty in
reliably estimating the dose of exposure in the mother and the fetus. Assessrnent of solvent
dose of exposure in the mother is dependent upon many factors that may have an effect on
reproductive outcome or may possibly interact with the effects of solvent exposure. In
quantifjmg dose of exposure, environmental variables (e.g. ventilation. temperature, duration
of exposure), characteristics of the individual (e.g. body weight, physical rxercise), as well as
effect-modifying factors such as smoking, alcohol consumption, the intake of drugs, and
exposure to other chernicals must be taken into account. The study of behavioural teratology
is m e r complicated by the difficulty in reliably assessing the dose of exposure absorbed by
the fetus. Thus, the calculated index of exposure employed by this study should serve only as
a crude estimate of actual exposure. It should be noted that an unreliable estimation of dose
may have given rise to misclassification of exposure level which, in tum, wouid have diluted
the effects of the exposure.
Another caveat in this study is the problem of accurate estimation of maternal solvent
exposure. Women's exposure to OS was estimated based upon their response to a series of
standard questions asked by a counselor at the time the woman contacted Motherisk dunng
her pregnancy. Not only is this method of exposure estimation crude, but the accuracy of the
estimated exposure index is dependent upon the woman's report. This method raises
questions of reliability because exposure information reported by each woman may Vary
depending on her familiarity with the chernicals or her anxiety over the pregnancy. For
example, a wornan who is highly concerned about the exposure may falsely attribute a feeling
of nausea due to the exposure when in fact it was an effect of the pregnancy. Thus, maternal
Prenatal Exposure to Orgaaic Solvents 53
report of exposure variables may not be useful in predicting outcome because any true
relationship may be diluted by invalid reports.
As part of this study, it was of interest to see how well women could recall
information about their occupational exposure dunng pregnancy. Materna1 recall of exposure
information could differ from the information reported at the time of the pregnancy due to a
matemal reporting bias, or an impaired memory resulting from the solvent exposure. X
cornparison of the exposure information obtained from the mother at the time of pregnancy to
that obtained at the time of the study is shown in Appendix L. Not surprisingly, the data show
large discrepancies with respect to reports oE duration of exposure, bamers used during
exposure, and whether symptoms were experienced upon exposure. One way in interpreting
these discrepancies is that there was a bias in retrospective ascertainment of exposure. But as
discussed above, even prospective matemal report cm be inaccurate. Nevertheless,
quantifjing matemal occupational exposure to OS through interviews may not be the most
reliable method of obtaining the information. These discrepancies need to be examined in
much more detail to detemine when the bias was greatest and why this rnay be so. Further
studies should explore the validity of using matemal report of occupational exposure in
behavioural teratology studies.
Another methodological consideration is in the interpretation of the CBCL results.
The CBCL showed that matemal reports of problem behaviours were considerably more
common among mothers in the exposed group than among mothers of the reference group.
This result could be due to a tendency in exposed women to rate theu chilàren as having more
pmblem behaviours compared to the refmt gmup. Women in the exposed group are more
likely to ahbute problem behaviours to the occupational exposure because they are biased by
Prenatal Exponirr to Organic Solvcnts 54
the exposure and they know their child is being tested for this reason. In order to understand
the real meaning of the difference in materna1 ratings of child behaviour, the children need to
be re-rated by another source such as a teacher.
The selection of the exposed group should also be considered when interpreting the
subtle differences between groups. One reason why the differences were subtle may be due to
the conservative selection OF the exposed group. The sample of c hildren in the exposed group
were regarded as a low-risk group because only full-term, physically n o m 1 children were
included. Children who were bom prematurely were excluded because of the possibility that
an observed relation between exposure and outcome could have been a spurious consequence
of gestational age. As prematurity is also a likely adverse consequence of prenatal toxic
exposure, we have restricted ourselves to the hardier population including those more resistant
to the effects of solvent exposure. Future studies should include children who were bom
premature by matching children for gestational age and using it as a mediating variable in the
relation of prenatal exposure to OS to developmental outcome.
Age at testing is another important variable in the interpretation of results in
behavioural teratology studies because outcome may Vary depending on the age of childe. The
choice to study young children between the ages of 3 and 7 was based on the lact that early-
age cognitive assessments of behavioural teratology outcome may be more sensitive than tests
in older children because of recovery processes and potential bbcatch-up". Functional recovery
fiom teratogen-induced CNS damage can occur by: neural reorganization, compensation or
substitution by brain areas less affectai by the exposure (cited in Hannigan, 1995). Since any
- -
9 Ideally, we would have Likcd to study an cvcn more restricted age mgc, but this could not be achievcd due to a smaii sample size.
Prenatal Exposure to Organic Solvents 55
or al1 of these recovery processes rnay be operating while the brain is still early in
development, neurotoxic effects may be exacerbated or ameliorated later on in development.
Therefore, we chose to investigate the effects of prenatal solvent exposure in young children.
However, the selection of young children, as opposed to older children, rnay also have
its shortcomings. Brain damage in urero has widespread potential for sorne degree of nsk tor
abnomal onset, rate of mastery, control and up-keep of each and every cognitive ski11
developed over the life span. According to Dennis (1988), the damaged developing CNS
should be viewed as a dynamic plastic system in which teratogenic outcomes are expressed as
processes of recovery. She argues that dysfunction is more likely to change its expression
over development than to disappear. For example, the onset of a skill rnay be delayed, but
once the skill is mastered, it rnay be less than what would normally have been projected. For
this reason, a follow-up in the children at an older age rnay yield variable, long-term sequelae
of early damage that were not detected at an early age. Thus, it is possible that neurotoxic
effects do not become evident until a later age, when complicated cognitive skills such as
reading begin to emerge.
A major limitation of this study is that the expenmenter was not blinded to the condition
of the childtO. It must be achowledged that an examiner who is aware of the child's condition
rnay bias the administration or the scoring of the tests. It is believed that experimenter bias in
the present study was more likely to have affected the results of the neuropsychological than
the vision tests because the response variables on the vision tests were less apt to be
'O Blinding was aot a d is t ic consequence of this research projcct due to the time and energy coostraints of a Masters projcct.
Prenatal Exposure to Organic Solvents 56
infiuenced by the experirnenter. This study attempted to decrease this bias by having a
blinded observer score the results of any subjective tests, including the Design Copying and
the Visuo-motor Precision subtests. Also, the three other examiners who tested approximately
20% of the children were blinded to condition.
Another limitation to the study is the selection of the exposed group. Because a
number of children h m the original smple were lost to follow-up, the exposed group cm
not be regarded as representative of the onginal sample. It should be noted, however, that
factors reflecting cases lost to follow-up (e.g. moving, changed phone numbers) were not
expected to systematically influence scores. The reader should also be cautioned that the
sample of mothers in the exposed group is not representative of ail pregnant women who work
with OS, and may in fact represent a more mildly affected group. Mothen who took the
initiative to contact the Mothensk program during their pregnancy are more likely to be more
conscientious about chernical exposure, and therefore may have taken greater precautions
against solvent exposure (i.e. used protective equipment, minimized length of exposure) than
the general population of exposed pregnant women. As a result, the exposed group in this
study may have inadequate exposure levels to produce noticeable neurobehavioural deficits in
their offspring.
Finally, due to the smail number ofwomen exposed to a particular type of solvent or
solvent c h , it was impossible to isolate the various OS and examine the effects of each
separately. This is a limitation of this study because it is well known that certain classes of
OS have different effects than others (Mergler, 1998). For example, aromatic hydrocarbons
are highly opthalomotoxic and rnay rapidly affect the optic nerve more so than halogenated
Prenatal Exposwe to Organic Solvents 57
solvents or alcohols. By grouping al1 types of OS together in the analyses, we can not specify
which are more h m h l types of solvents.
Our findings offer exciting new questions for hiture research* As mentioned above, one
particularly important area bat needs to be fùrther studied is the effects of prenatal exposure
to a homogeneous class of OS. This is critical bccause information about specific effecrs of
OS will help determine which types of occupations are at increased risk of neurotoxicity.
Forthcoming studies should work closely with health officiais who can provide reliable
measurements of exposure to OS dunng the tirne of pregnancy. Ideally, quantitative measures
of solvent concentration in ambient and expiratory air, or measures of metabolite excretion in
the urine must be obtained at the time of pregnancy in order to establish reliably a dose-
response relationship for particular solvents.
In addition to neuropsychological tests, neurophysiological techniques such as visual
evoked potentials (VEPs) or electroretinograms could be used to investigate more directly
nervous system functions that may be additionally impaired. Not only do these techniques
serve as objective and reliable methods of evaluating neural activity, they cm also provide an
unprecedented o p p o d t y for linking brain lesion with outcorne. Research using
electrophysiological strategies is critical for linking neurotoxic darnage to brain structure and
fiinction.
Clearly, more research examining the efiects of prenatal exposure to OS is necessary
for determining the long-terni effects of early exposure over the lifespan. Long-term or
subsequent follow-ups on these children should be performed with tasks involving greater
cognitive demands as well as a variety of other areas (e-g. memory, anthmetic). Furthemore,
Prenatal Exposure to Organic Solvents 58
effects of prenatal exposure to OS should be compared with the effects of prenatal alcohol
exposure as a starting place. M e r all, alcohol is a soivent, and studies on toluene abuse have
show similar effects as those found in fetal alcohol syndrome (Pearson et al., 1994).
Research should examine whether deficits resulting fkom materna1 occupational exposure to
OS resemble deficits found in children with alcohol-related birth defects. By using
biobehavioural markers of neurotoxicity found in the vast number of audies on prenatal
alcohol exposure, we cm get evidence of whether the nvo exposures share a similar
pathology. If there is an association between these exposures with respect to pathway
disniption and neural deficits, Our undentanding of the effects of prenatal solvent exposure on
the developing CNS may potentially be advanced much laster than previously thought.
This investigation provides unique insights into the effects of OS on the developing
CNS. Our findings suggest that prenatal exposure to OS may be related to subtle alterations
in ce11 proliferation or migration during early CNS development. The results of this study are
also relevant in Furthering our understanding of the extent of visual development before birth.
For instance, an analysis of the time of exposure and the presence of a colour vision
deficiency cm yield information about the organogenesis of the visual system's components.
Further research in this area will advance our understanding about critical periods in
neurodevelopment.
The importance of routine screening following neurotoxic exposure in young children
is emphasized based on the results of the present study. By using quantitative measures of
visual and acoustic ability, subtle effects of neurotoxic exposures rnay be detected early in
life. This is important because knowing that a cbild bas a visual or acoustic deficit may
Preoatal Exposure to Otganic Solvents 59
facilitate the child with respect to Iearning and adaptation. For exarnple, if a teacher is aware
of a child's colour discrimination deficit, the use of colour as a teaching tool may be avoided.
Furthemore, leaming can be facilitated by helping a child with colour vision defects learn to
use other cues to detect colour differences or by altenng visual displays to be more visible.
Finally, if research shows a trend of an increased risk of visual and / or neuropsychological
impairments among solvent-exposed children, health professionals, such as cyc carc clinicians
and child psychologisrs, will be better equipped to detect and diagnose the dyshuiction in
early childhood. It will also be critical For specialists to inquire about prenatal exposures
when deficits are suspected in children.
Our tindings show an increased Rsk of adverse effects on visual and cognitive
development following matemal occupational exposure to OS dunng pregnancy. Although
the findings of the present study do not signim causality, the discovery provides suppon for
an important working hypothesis that matemal occupational exposure to OS during pregnancy
is associated with "subclinical" deficits (i.e. cognitive and visual deficits in normal
intelligence children that would not necessarily be evident in an informa1 clinical
examination) in the offspring in the absence of physical malformations. Until replicated,
however, these findings should be treated as preliminary. We conclude that it is worthwhile
to Collow-up chilàren exposed to OS in utem, even when the level of exposure is low and the
degree of deficiency is mild. With further research in this area, we can hope to identify what
particular OS are most h a r d 1 and what level of exposure is not teratogenic. Understanding
the risk of matemal occupational exposure to OS will have implications for potential
interventions of teratogenic exposures and will heîp establish safety guidelines for pregnant
women exposed to OS at their workplace.
Prenatal Exposun to Organic Solvent6 1
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Table 1
Block Test
1 NEPSY Subtests:
Body Part Naming
Design Copying
Phonological Processing
Comprehension of Instructions
Visuo-motor Precision
B lock Construction
Statue
Verbal Fluency
EOWPVT-R
WRAVMA Pegboard test
WRAVMA Matchhg test
PPVT-III
Continuous Performance Test
Cardiff Cards
Minimaiist Test
Table 2
BIock Test
NEPSY Subtests:
Design Copying
Tower
Arrows
Speeded Naming
Phonological Rocessing
Comprehension of Instructions
Visual Attention
Visuomotor Precision
Statue
EOWPVT-R
WRAVMA Pegboard test
WRAVMA Matching test
PPVT-III
Cardiff Cards
Minimallst Test
Continuous Performance Test
Table 3
Occupation
Factoq worker l Machine operator
Laboratory worker 1 Technician
Graphic designer
Dry Cleaner
Ph0 tograp hic development
Artist 1 Art teacher
Chemist
Cat prep Uidustry 1 Paint plant
ûperating room penonnel 1 ûccupat. Therapist
Solvent Exposure
Halogenated Solvents
Aliphatic Hydrocarbons
Aromatic Hydrocarbons
Complex Solvents
Alcohols
Aîdehydes
Glycols
Table 4
Women
No. of years of education
Hollingshead Score
Age at delivery * No. months breast-feding infant
Mother breast-fd infant (%)
Smoked cigarettes (%)
M d e d at follow-up (%)
C hildren
Gender (% female)
Gestational week at delivery
No. of days in hospital after birth
Child's age (yrs) at testing
Birth Order: First bom (%)
Mer Demographic uiforrnation
Live in d a n environment (%)
FACES-pl Cohesion Score
FACES-III Adaptability Score
Ethnicity: North Amencan (%)
Table 5
Begin to Crawl * 7.33 1.55 29 8.77 2.60 26
Begin to Walk 12.71 2.60 3 1 13.31 4.14 26
Begin to Run ** 19.83 6.77 23 14.38 4.22 21
Speak First Words 13.00 4.30 26 15.91 7.12 22
Use First Sentences 20.88 6.41 24 22.20 7.08 15
Table 6
Males Growth
Weight (ibs) 46.04 10.87 15 44-64 6.73 13
Height (cm) 109.53 9,95 15 111.18 9.33 13
Head circurnf. (cm) 52.96 1.12 15 52.15 1.24 13
Fernales Growth
Weight (lbs) 41.99 8.52 t 6 42-97 6.34 14
Height (cm) 107.75 9 3 16 110.38 9.25 14
Head circumf. (cm) 5 1.63 1.42 16 51.23 1.94 14
Table 7
Narrow Band Syndromes
Sleep Problems
Withdtawn
Somatic Cornplaints
Anxious 1 Depnsseâ
Social Problems
Thought Pmblems
Attention Problems
Delinquent Behaviour
Destructive Behaviour
Aggnssive Behaviour
Intemalizing h b l e m s
Extemalking Problems
Total Probtems
Prcnatal Exposurc to ûrganic Solvents 8 1
Table 8
* Incrcasing score rcflects gratter chromatic discrimination dtficit
Table 9
Score * Exiipppd
Deutan Protan Tritao Deutan Protan Tri t an
* Increasing scotr tcflects p a t e r chromatic discrimiaation dcficit
Table 10
Sc- for
Receptive Language 0.338 0.738 0.627 0,626 -1.632 59 0.108
Expressive Language O. 173 0.685 0.696 0.728 -2.889 59 0.005
Visuo-spatial Ability 0.020 0.797 0.375 0,802 -1.727 59 0.089
Fine-motor Ability -0.13 1 0.779 -0.1 18 0,788 -0.063 59 0.950
Graphomotor Ability -0.450 0.993 -0.149 0.905 -2.442 59 0.018
Attention 0.349 0.709 0.336 0.595 0.076 58 0.939
Table 9
Subtcst
Receptive Language
PPVT-IF 0.309 0.849 0.588 0,844 -1.282 59 0.21
Comprehensioa of Instructions 0.542 0.798 0.702 0.828 -0,765 58 0.45
Phonologicd Processing 0.167 0.964 0.611 0.802 -1.534 36 0.11
Expressive Language
Speeded Naming -1,167 1.199 -0.100 1.228 -1.965 18 0.07
EOWVT-R 0. 188 1 .O00 0.843 0.880 -2.692 59 0.01
Body Part Naming 0.400 0.746 0.843 0.883 -1.655 35 0.1 1
Verbal Fluency 0.469 0.780 0,782 1.107 -1,262 56 0.21
Prcnataf Exposurc to Organic Solvents 85
Table 10
Variable
Phonological Processing 0.57 9.78 0.002
Length -1.50 0.41 -3.61
Exposure Index -0.32 0.10 -3.62
Comprehension of Instructions 0.43 6.38 0.002
Length -0.61 0.27 -2.23
S ymptom -0.40 0.15 -2.65
Duration -0.50 0.28 -1.77
PPVT-III
Ventilation
Exposure Index
EO WPVT-R
M. "Lcngth" rcftrs to a wcightcd d u c with high values rcpresmting fiiU tcrrn cxposurc, "Symptomn reftrs
to the nuniber of adverse cfftcts asmciatcd with solvcnt cxposurc during pregnancy, "Duration" refers to a
weighted value rcpmcnting number of houn worlccd pcr wctk, "Exposwc Index" rcprescnts the intcnsity of
exposure assigncd to tach woman calculatcd using an algorithm of weighttd factors known to affect dose of
cxpo-.
Plenatal Exposure to ûrganic Solvcnts 86
Table 11
Subtest
WRAVMA Matching Test 0.42 1 0.964 0.555 0.999 -0.528 58 0.60
B lock Construction -0.323 1.043 0.310 0.968 -2,440 59 0.02
~ O W S -0.077 0.818 0.273 0.800 -1,054 22 0.30
Prenatai Exposurt to Olganic Solvents 87
Table 12
Subtest
Finemotor Skiils
Hand Positions -0.471 0.884 -0.487 1.088 0.060 53 0.95
Pegboard Test (dominant hand) 0.202 1 .O8 1 0.202 1 .O32 -0.001 59 0.99
Graphomotor Skills
Design Copying -0.091 1.191 0,548 1.187 -2.090 59 0.41
Visuo-motor Precision -0.808 1.014 -0.250 0.996 -2.159 59 0.04
Prcnatal Exposure to ûrganic Solvents 88
Table 13
Variable
Design Copying
Ventilation
Exposure Level
Visuo-rnotor Precision
Length -0.93 -0.93 -2.88
S ymptom -0.29 -0.21 -1.39
Table 14
Subtest
Statue 0.462 0.713 0.166 0.855 1,424 55 0.16
Tower 0.615 0.837 0.364 1,005 0.670 22 0.51
Visual Attention 0.062 1.116 0.405 0.650 -1.437 59 0.16
Prcnatal Exposure to Organic Solvcnts 90
Problem Behaviour
Pimiatal Exposurc to Otganîc Solvents 9 1
Binocular Monocular
2 - B. Monocular
Colour Confusion Line
Binocular Monocular
Prcnatai Exposure to Organic Solvents 94
RESEARCH INFORMATION
Date of Blrth:
HSC #:
Matemal Occupational Exposure to Organic Solvents During Pregnancy and Subsequent Visual and Cognitive Development in the Child: A Prospective Controlled Pilot Study.
Christine Siambani, BSc. Research Coordinator, University of Toronto, Dept. of Psychology (416) 813-7654 ext. 4343
Dr. Joanne Rovet, Ph.D. Professor and Senior Scientist Dept. of Psychology, University of Toronto Dept. of Psychology, The Hospital for Sick Children Phone: (41 6) 8 13-7442
Dr. Cideon Koren, M.D. Director and Professor Div. of Clinical Pharmacology and Toxicology, The Hospital for Sick Children Phone: (416) 813-5778
Many women are exposed to solvents in workplace settings, such as laboratories, factories, or the printing industry. The purpose of this study is to study the relationship between minor occupational solvent exposure during pregnancy and children's early developrnent. At pcesent, most information about the effects of solvent exposure cornes h m studies in adult workers. It may be possible that chilcûen whose mother's were exposed to solvents have different rates of developmmt than children whose motha's were wt exposed to solvents. We feel it is important to snidy whether this relationship exists. In this shidy, we want to see if children of mothers exposed to solvents are able to solve problems in attention and verbal ability at a level appropnate for their age. Also, we want to see if these children have normal colour vision and other skills related to the visual system that are appropriate for their age. Research in this area is important to understaad the nlationship between solvent exposure duriag pregnancy and children's development.
Prenatal Exposurc to Organic Solvents 95
Appendix A Continueci
This study will compare a group of 3 to 7 year old chilchen whose mother's were exposed to solvents with a similar group of children whose mother's were not exposed to solvents during pregnancy. Children will be asked to corne to the Hospital for Sick Children for a 2 hour testing session (includiiig breaks). We will test colour vision, visual acuity, attention, verbal ability, fine motor skills, and spatial abilities. Most tests involve participation in a game-like situation where the child is asked to point to objects or copy picnim.
Although we expect no h m , your child rnay experience some discornfort being in a new situation and an unfarniliar setting. Also, it rnay be an inconvenience to get to the Hospital for Sick Chilàren or to find t h e in your schedule to participate in the snidy.
It would be beneficial to be aware of any colour vision loss a child rnay have for several reasons. Firsf howing a cbild experiences colour problems would help the teacher understand any difficulties the child rnay have in learning. Second, if a child is aware of this impairment, he or she will be able to l e m to use other cues to detect differences among colours. It should be noted that if colour vision loss is suspecteci, a refenal to an eye doctor for m e r examination will be provided.
In addition, the test battery will give you information about your child's ability on specific tasks of attention, verbal ability, fine motor skills, and spatial abilities. Upon completion of the study, you will receive a report descniing your child's results which rnay be usehil in later educational planning. If a problem area is identified, we will share this information with you, and provide recommaidations for improvement.
Society in g e n d also benefits h m your participation in this study. Doctors will be better able to aâvise mothers who are exposed to organic solvents at their workplace on any potential risks to her baby. This rnay help d u c e anxiety among pregnant women, and rnay mult in counseling opportunities for fiinire pregnancies. Lastly, research in this area rnay have implications for changes in workplace regulations for pregnant women.
Confidmtiality will be respectecl and no Uiformation that reveals the identity of you or your child will be released or published without your consent. The resuits of the tests described above will be used for research purposes only in the context of this study. We would need your permission and signed consent to send these test scores to another professional involved in your care. For your information, the research consent fonn will be inserted in the patient health record. We recommend that the results of these tests be interpreted by a registered psychologist or physician.
We will nimburse you for any transportation andor parking costs that are incurred b y participating in this study.
Participation in research is voluntary. If you choose not to participate, you and your family will continue to have access to quality care at HSC. If you choose on behalf of your child to participate in this sîudy you can withdraw your child fiom the sîudy at any time. Again, you and your family will continue to have access to quality care at HSC.
If you wouid like to know the source of fuading, please discuss this with any of the investigators: Christine Siambani at (41 6) 8 13-7654 ext. 4343, Dr. loanne Rovet at (4 16) 8 13-7442, or Dr. Gideon Koren at (416) 813-5778.
Appendix B
RESEARCH CONSENT FORM
Date of Birth:
HSC #:
1 acknowledge that the research procedures described above have been explained to me and that any questions that 1 have asked have been amwered to my satisfaction. 1 have been informai of the alternatives to participation in bis stuciy, including the nght not to participate and the right to withdraw without compromishg the qudity of medicd care at The Hospital for Sick Children for my child and for other members of my farnily. As well, the potential harms and discornforts have been explained to me and 1 also understand the benefits (if any) of participating in the research study. 1 know that 1 may ask now, or in the htwe, any questions 1 have about the study or the research procedures. 1 have been assured that records relating to my child and my child's care will be kept confidentid and chat no information will be nleaseâ or printed that would disclose personal identity without my permission unless required by law.
1 hereby consent for my child to participate.
The Person who may be contacted Narne of Parent about the research is:
who may be reached at telephone #:
Signature 3-7654 a 4343
Name of person who obtained consent.
Signature
Date
Appmdix C
Outcome of Follow-up
- - -
No. of women iost to follow-up 52 44.4
Women contacted 65 55.6
Women who w m excludeci at time of screening
Woman removed h m exposure 3 4.5
Women exposed to other chernicals 2 3 .O
Non-occupational exposure to solvents O O
No. of women with endocrine dysfunction 2 3 .O
No. of women with depression 1 1.5
No. of non-English speaking fimilies 1 1.5
No. of women with neurologicai abwrmality O O
Pregnancy les than 36 weeks 1 1.5
Pregnanc y resulted in rniscaniage 4 6.0
No. of children who were not testables+ 1 1.5
No. of women sent uiforrnation 50 42.7
No. of women agreed to participate ' 35 70.0
No. refiscd to participate 15 30.0
No. of woman who missed appointment 2 4.4
Total no. of children teste& 37 33
Reasons why children were excluded after testing:
Child uncwperative O O 2 6.1 '
Child bom premahue ( 0 6 weeks) 2 5.4 1 3 .O
Family history of visuai defects Ob O 1 3 .O
Complication during pregnancy 1 2.7 1 3 .O
Maternai use of recreational dnigs 1 2.7 O O
Total no. of children included in study 33 28
Each wonitn was sckctcd as a potential coniml based on theu cxposurc information obtaincd at the time of
pregnancy. ûniy women and their chiidrm who matchcd a pair in the exposcd group werc asked if thty wcrc
interestcd in participating.
+* one autistic child (expostd); 1 child witb cpilcpsy and 1 child with leukania (controls)
* calculatcd as a petcentagc of women who wete sent Uiformatioa
' of the 37 exposed chiidrtn, 4 wem siilings; of the 33 control childrcn, 8 were Jiaihgs
calculatcd as a pcrccntage of womcn who wert sent idonnation
one chüd with congcniîai colour vision los was excluded h m the visual fùnciioning tests child fell aslccp and
1 child was hypctactive and did not complete mort tban half the tests
PaUent's N m t
Hom phwc Workphont
D e of b i i Amnio? Y& No0 Advisedo
Memdby: H c r l t h d #
Stable Conw # nrliriwlila:
Currcrit MDJtype= pa0ne:
OccuMli011:
NOT PREGNANT gcami UiCoO P-8 0 ietrospbctiv~0 b r r u t f i g o
(-1 evuy &ys Ccrcrin? Y N
Cumfy: weight kg lb gtrtrtion wk moi
cm byd-oby-0
iNCûMING: date: thne
counseuoc
compIcktî 0 passcd LO leUow0
OUTGûiNG: date: tinte:
completcd b y
-Y No0 Ycs Hmt No0 Ytr
Hyputamioa N o 0 Yer
Di&eîcs No0 Yca
R ~ ~ ~ w c Y N o 0 Ycs
Tbymid N o 0 Yes
Psychurric N o 0 Ytr
epicpry No0 Ytr
Vi~supplemeaution? No0 Yu:
Oi&r
-w ! WRMQpslaricy 4
I Cocaine, Crack- m m ~ ~ VW-W
Marijuana -(rrqug
m r : DURM(3Rlirrr 1
O Chlamydia OChiclrcn port O W t a l h e r p e s mononhea OCortsaclQe ~Hepatitis B OHLV OParvovinis B 19 OSyphiüs O Vm"alla mtr.
Type of contact: oblood Odiycue of& Obouschold Ohospitai Owiîb lesions O mucoul 0 d orexwl O*
Patient had disease in the past 0 Distase ciinidy d i a g d ? Ng) Yeso by
Refercaced advice +box on pg. 1
C)icmicrl: Occupation: ,Y
Referenced advice + box on pg.1
Numkr of times brcostfed daily: how often?
Date of birth: Gestational age at birth: wk Birth weight: kg lb F o r m a supplemeatption? Yes No Solids? Yes No
name w Am you taking mcdication as p d b e d ? age stnrted age starttd Yes No # timeslday U t i d d a y
Th6 infonnation is confidential and for professional use only. Please fill out as completely as possible.
Name of child: Date of bùih (ciMy):
Name of pmou completing fom:
Mother's Namt: Biological Fatheis name:
Address: Addrtss: check if same as mother [ ]
Home phone:
Work phonc:
Age:
Occupation:
Highest grade complctcd:
Home phone: samc [ ]
Work phone:
Age :
Occupation:
Highest grade completcd:
Language spokcn most 0 t h at homc:
Eutopean Paternai ethnlcity: [ 1 European Afncan [ 3 Alkan North Anmîcan [ ] North AmCncan Asian Indo-Asian
[ 1 Asian [ j Indo-Asian
1 Latin [ 1 Latin l Wei. (specisr) [ 1 (specisr)
Marital Statur: Marricd [ ] Scpmted [ ] Divorccd [ ] Widowcd [ ] ûthtr [ 3 Namt of petson who spenâs most timt with child:
Do any other miatives livc at homc? Please dcscrik.
Please describe reasons for medication, details about medical condition and the name of the prescn'bing physician for any medication taken during pngaaacy.
Dnig Namt Caicndar start date Calendar stop date Drug dose Route
B. Job J
1.
2.
3.
Occupation during pregnancy:
[ ] ongoing txposurc
j ongoing cxposurc
[ 1 ongoing cxposum
Length of ernployment at h e of pregnancy:
v o ~ o c c u m : [ ] physical effort [ ] mental concentration / attentional demands [ ] repetitive motion [ ] manuai dextetiîy [ ] time pressure
* . e: [ ] expoexposed to irritants such as dust and other chernicals [ ] high temperature or hmidity in workplace [ 1 Poor üghting [ ] loud noise [ ] cmwding [ ] shift hours worked
Date returned to work after pregnancy:
Name of chemical(s) exposed to during pregnancy @leuse indicote which exposure(s) are prinrary (in same area where chemical used) and secondury (indirect exposure):
Start date of exposure: [ ] present at start of gestation [ ] other (specib)
Stop date of exposun: [ ] specify number of months pregnant: months [ 1 other (specify)
Duration of exposun: [ l h r s l d a ~ x - number of days per week
Ventilation during exposure: [ ] none [ ] fumehood [ ] general - wdl & roof fan, ceiling vent [ ] natuni1 - open windows & door
Barrien during exposure: [ ] gloves [ ] apmn, helmet [ 1 mask [ 1 go~gies [ ] respirator [ ] other
Could you, or other empioyecr, smeU or taste cbemical vapors during work? [ ] no [ ] yes
Side e f f i t s during exposure: [ ] none [ ] visuai irritations [ ] diarrhea [ 1 rash [ ] dininess [ 1 na- [ ] headache [ ] (spe~i@)
hnatal Exposure to Organic Solvents IO5
Appendix E Continued
Alcohol [ ] No [ ] Yes How many drinlrs? per [ ] day [ ] week [ ] month
Date alcohol co11sumption stopped: when pregnancy diagnosed [ ] Addi tional information:
Cigarettes [ ] No [ ] Yes How many? per [ ]day [ ] week
Date tobacco exposure stopped when pregnancy diagnosed [ ] Additionai information:
Recreational Drags: Please describe type(s) of h g , fiequency of use, and at what month of pregnancy use was stopped (if applicable).
Was the father taking any medications or dmgs at the tirne of conception? if so, what?
Anaestheda duringpregnancyng y [ 1 No [ 1 Yes type: date@) of exposure:
Radiation during pregnancy [ ] No [ ] Yes type: date(s) of exposure:
Did you have any injuries during your pregnancy? [ ] No [ ] Yes Please explain type of injury and when it occumd.
Appenâix E Continueci
Kidney Heart disease Diabetes Epilepsy Hematologic Hypertension Psychiatric Neuro logic Respiratory Thyroid disease Vitamin supplementation Other (speciQ)
Do you Wear glasses? N [ ] Y [ ]
Is the biological mother colour blind? N [ ] Y [ ]
1s the biological father colout blind? N [ ] Y [ ]
Do you have a family history of acquired or congenital colour vision loss? N [ ] Y [ ]
B. w ' s M-
Name of family physician I pediatrician who has pnmary care of child:
Doctor's address:
Date of child's last physical exam:
Please describe any periods of ihess or hospitakation (injuries, accidents, operations, convulsions, allergies, ear infections, etc.)
Has your child had his / her vision checked? [ ] no [ ] yes I f yes, by whom? Date: Finding : Glasses: [ ] no [ ] yes
Has your child had any special medical examinations (Le. neurological)? [ ] no [ ] yes Please specify.
Does your child take any routine medication? [ ] no [ ] yes
Curent medication:
What for?
Cumnt medicai problems:
C* Pmaiaev
Length of pregnancy (in weeks):
Any illness or complications while pregnant? [ ] no [ ] yes
tf yes, please explain:
D* - Was the biith of the child 'normal'? [ ] no [ ] yes Infant home at days.
Ifno, please explain.
Was your child bom: [ ] mahue [ ] prematurr (less than 36 weelrs)
Appendix E Continued
Requirement of resuscitation or nanatal interisive care unit? [
Problems following birth (please describe):
Brest feeding [ ] no [ ] yes aonle feeding [ ] no [ ] yes
started at days stopped at days started at days stopped at days
crawl:
fed self with spoon:
used single words:
potty trained / day:
waik alone:
scribbled:
used sentences:
potty ûained / night:
ran well:
tied shoes:
Does your child have any language difficulties? [ ] no [ ] yes
Please describe:
Do you see the child as being [ ] hyperactive? [ ] inattentive? [ ] a behavioural problem?
Please explain:
Prenatal bposurc to Organic Solvcnts 109
IV. I f 1 or- . .
Nail biting
Thumb sucking
Bed wetting
Sleep problerns
Tantnuns
Abnormal aggressiveness
Pronounceci disobedience
Destnictiveness
Overactivi ty
Pst [ 1 present [ 1 past [ ] present [ ]
past [ ] present [ ]
past [ ] present [ ]
past [ ] pnsent [ ]
past [ ] present [ ]
past [ ] present [ 1 past [ ] present [ ]
Pst [ 1 present [ 1
Name of sibling(s): Age Sex Grade Live at home?
How are sibling nlationships? [ ] good [ ] fair [ ] poor
G* * P lease add any additional comments you think might be helphil.
Signature: Date:
Relationship to child:
Inunkpu for tuking the rime to compfete th& form.
Appmdix F
Social Shta for the Hollingsheod Four-Facor Inder ofSociocconomic Statu
Social Strata Range of Computed Scores Level
Major business and profcssional 66 - 55
Meâium business, minor professional, technical 54 - 40
Skilled craftsmen, clencal, sales workea 39 -30
Machine operators, semisicilleci workers 29 - 20
Unskilled laborers, menial service workers 19-8
Appendix G
FACES III
David H. Olson, Joyce Portner, and Yoav Lavee
1 2 3 4 S ALMOST NEVER ONCE iN AWHILE SOMETiMES FREQüENTLY . ALMOST ALWAYS
DESCRIBE YOUR FAMILY NOW:
Family mtmbcrs ask cach other for help.
In solving probltms, the childrcn's suggtstions arc followed.
WC approve of each othcr's f r i tnds
Childrcn have a Say in thtir discipline,
We likt to do things with just our immediate family.
DiTferent persons act as leaders in our family.
Family membtrs Ceel clostr ta other family members thrn to people outsidc the f'amily.
Our family changes itâ way o f hondling tasks.
Family memben tikc to spend frcc time wifh each other.
Parcnt(s) and children discuss punishmcnt togethcr.
Famity membcn fetl very close to each othtr.
The childrcn makc thc decisions in our family.
Whcn our family gets togcther for activities, cvcrybody is prescrit.
Rulcs change in Our Tarnily.
WC can easily think of things ta do togcthcr as a fnmily.
WC shift household rcsponsibilities from pcrson to pcrson.
Family membcrs consult othcr family mcmbers on thcir decisions.
It is hard CO idcntify thc lcodcr(s) in our family.
Family togcthcrncss is vcry importan t,
It is hard to tell who does which household chorcs.
FAblILY SOCIAL SCIENCE, 290 ~ c ~ c a i Hall, University a l Miiirrita, St. Paul, hlN 55108
@ D.H. Olson, 1985
Appendix H
Ranges of FamiS, Adaptability and Cohesion Evaluation Scala (FACES)
Family Cohesion Range of Scores Family Adaptability Range of Scores
Disengaged IO- 34
Separated 35 -40
Connected 41 - 45
Enmeshed 46 - 50
Rigid 10 - 19
S tnictured 20 - 24
Flexible 25 - 28
Chaotic 29 - 50
Appendix 1
Test Pmtocol for Young Children (aged 3-4 years)
Verbal Ability
NEPSY Body Part Narning Naming of body parts depicted on a picture
NEPSY Phonological Processing Sound blending and word completion tasks
NEPSY Comprehension of Instnictions Process and respond to verbal instructions
NEPSY Verbal Fluency Ability to generate words within a category
EOWPVT-R Naming of objects depicted in line drawings
PPVT-III Receptive language test; Predictive of verbal I.Q.
WRAVMA Pegboard Test
NEPSY Visuo-motor Precision
NEPSY Design Copying
NEPSY Imitating Hand Positions
WRAVMA Matching test
NEPSY Block Construction
Attention
NEPSY Visual attention
NEPSY Statue
Insert pegs into a grooved pegboard within 90-sec.
Draw a continuous line on a curvilinear route
Drawing two-dimensional geometric designs
Ability to reproduce a hand position h m a mode1
Identification of picnins conesponding with test item
Assembly of blocks to replicate 2D representations
Measms speed and accuracy in locating a target
Ability to stand still in a set position over a 1 1 5 sec.
Mollon-Refi-Miriirnalist Test Measures colour vision discimination
Cardiff C d Acuity Test Assess visual acuity using high fkquency test
Appendix J
Test Protocof for Children (uged 5-7years)
Verbal Ability
hTPS Y Phonological Rocessing
NEPSY Spcaded Naming
NEPSY Verbal Flumcy
EO WPVT-R
PPVT-III
Visuo=Motor AbIUty
WRAVMA Pegboard Test
NEPSY Imitating Hand Positions
NEPSY Visuo-motor Precision
Sound blending and word completion tasks
Assess aaming ability; rapid access to and production of
narnes of recufnng colors, sizes, and shapes
NEPSY Comprehmsion of lnsüuctions Process and respond to verbal instructions of
incnasing syntactic complexity
Ability to generate words within specific categones
Naming of objects depicted in line drawings
Receptive language test; Redictive of verbal I.Q.
Numba of pegs inserted within time limit
Ability to reproduce a hand position h m a mode1
Ability to draw a continuous line on a curvilinear
mute as quickiy as possible
NEPSY Design Copying Drawing two-dimensional geometric designs
Domain Description
VisuoSpatial Procesrhg
WRAVMA Matching test
NEPSY Arrows
NEPSY Block Construction
Attention
NEPSY Tower
NEPSY Visual attention
NEPSY Statue
Vlruai Functioning
Minimalist Test
Cardiff Acuity Test
Identification of pictures which correspond wiîh test item
Judge Üne orientation and directionality
Assembly of 3-D blocks to replicate 2-D
representations of designs
Assess nonverbal problem-solving abilities
Measures speed and accuracy in scanning an
anay and locating a target
Ability to stand still in a set position over a time
period while inhibiting response to distracton
Assess chromatic discrimination capacity
Assess visual acuiîy
ueparrrnenr or upnrnainioiogy Visuaf EIectrophysioIogy Unit Carof Westall PhD
Name: Cardiff Acuity Norms ,,,: *' 6 95 % lirnits Date:
Date fEye Tested
Age (months)
+Log MAR Acuity Score
Card : 1 2 3 4 5 6 7 8 9 10 11
2 rnetres 0.3 0.4 O. 5 0.6 0.7 0.8 0.9 1 .O 1.1 1 .2 1.3
Binoc O Test Distance Card giving Acuity Hm it Confidence?
O=lowest; 1 O=highest
Appenâix L
Case History: Maternai Occupational Solvent Exrposure In formation
According to the information provideci to us, Mrs. X was worked as a machine
operator in a printing factory for the full terni of her pregnancy. Her work involved physical
effort, mental concentration, repetitive motion, manual dexterity, and tirne pressures.
Conditions at her work hclude exposlne to chemicals, high temperature, poor lighting, loud
noise, and crowding. Mm. X had been employed at the factory for 7 years pnor to her
pregnancy with Joshua Mrs. X had inhalation exposure to methyl ethyl ketone (MEK),
silicon, and ink strippers, up to 10-hours a day. 4 days a week. She did not use any
protective barriers and her workplace was ventilated only with nahiral measures (Le. open
windows and a door). Mrs. X could detect the chernical fumes and she complained of
numemus adverse effects including dizziness, headache, visual irritations, nausea, trouble
breathing, and mucousal buming. She stated that she felt her symptoms were worse than
those of her workplace colleagues. Mrs. X retumed to her employment as a machine
operator approximately 10 months after Joshua was bom.
Appenk L Continued
According to the information pmviâed to us, Mrs. Y was working as a laboratory
technician in a paint factory for the full term of her pregnancy. Mrs. Y had been working in
the colour-mstching room as a colour fomulator for approxirnately 4 years prior to her
pregnancy. Her office was separateci by a closed door from a larger room where paint and
solvents were mixed under fume hoods. Adjacent to that area was a larger area where the
production and testing of the paints occurred. Mrs. Y sometimes tested products in the spray
booth which was in this larger ana. On average, she worked 6 hours a day, 5 days a week.
Mrs. Y provided Motherisk with a fairly extensive List of chemicals. Some of the major
chemicals she worked with include: toluene, xylene, lacquer solvent, naptha, varsol, methyl
ethyl ketone, acetone, ethanol. aicohols, isocyanates and epoxies. Mrs. Y wore gloves,
protective clothing, a respirator, and goggles when handling the chemicals. Although she
could detect organic solvent fumes and an ammonia srnell, Mrs. Y did not report any adverse
effects upon exposure to the chemicals.
Prcuatal Exposurc to ûrganic Solvcnts t 19
Appendix L Continued
According to the information provided to us, Mrs. Z was workhg 7.5-hour shifts, 5
days a week, as a sample coordinator chemist for the full temi of her pregnancy. She
perfonned quality assurance testing which required physical effort, mental concentration,
repetitive motion, manuai dexterity and time pressures. Although Mrs. Z handled the
chemicals under an adequate fumehood ventilation system, she could still srne11 the chemical
hunes. She used protective bamiers including gloves, a lab coat, goggles, and a mask and
respirator when necessary. Mn. Z fbquently workeâ with acetonitrile (1-2 hodday x 3-4
d/wk), acetic acid (2 xlwk), methanol, butanol, ethanol, chlomform, hexane, perchloric acid,
hydrochloric acid, and sodium hydroxide. To a lesser degree, she also worked with pyridine,
toluene, ammonium hydroxide, and tetrahydrofuran. Mrs. Z did not report experiencing any
adverse effects upon exposure to the chemicds.
Appendix M
Matemal Report ofExpomre Information Obtained ut The of Pregnancy (before)
and ot Time of Sludy (1 999).
* Duration refm to the number of hours per week
o Burkn refers to the numkr of protective masures used upon exposure to the solvents - Side effects refen to the numkr of adverse symptoms eXpenenced upon exposure to solvents