Pesticides, lead and solvents: pregnancy outcome and fertility Markku Sallmén Finnish Institute of...
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Transcript of Pesticides, lead and solvents: pregnancy outcome and fertility Markku Sallmén Finnish Institute of...
Pesticides, lead and solvents: pregnancy outcome and fertility
Markku Sallmén
Finnish Institute of Occupational Health
Pesticides
The most extensively used group of toxic chemicals
ca. 600 different active ingradients about 50,000 various formulations simultaneous exposure to different
chemicals typical pesticide formulations may contain
solvents
Pesticide exposure in farming
Most of the exposure occurs via the skin Some pesticides degrade on the leaves into
more toxic compounds with even stronger penetration capacity
Inhalation during applications Mixing, formulation, spraying, handling of
treated plants, cleaning of equipment and clothes, storage
Pesticides
Comparison between studies difficult Different pesticides are used for different
purposes and in different areas Exposure levels vary considerably; the
highest exposures occur in developing countries in poorly controlled circumstances
What is the affected gender?
Pesticides shown adverse effects on spermatogenesis
DBCP 2,4-D (2,4-dichlorophenoxy acetic acid) ethylene dibromide chlordecone carbaryl
Pesticides and semen quality
Study Outcome Larsen et al 1998 (longitudinal study) – multiple outcomes Larsen et al 1999 (organic/traditional) – multiple outcomes Padungtod et al 1999 (factory workers) + aneuploidy Tielemans et al 1999 (inf clinic clients) (+) combined quality Juhler et al 1999 (dietary pesticides)– dead spermat. Oliva et al 2001 (infertility clinic clients) + multiple outcomes Abell et al 2000 (greenhouse workers) + concent./morphol Wong et al 2003 (population based) + oligozoospermia Dalvie et al 2003 (DDT, malaria control) – multiple outcomes Swan et al 2003 (population based) + summary of many Sanchez-Pena et al 2004 (organophos.) + sperm chromatin+ = reduced semen quality, (+) suggestive association– = no association
Pesticides and male fecundability
Study Association de Cock et al 1994 + Larsen et al 1998 - Thonneau et al 1999 - Curtis et al 1999 (+), gender? Petrelli et al 2001 + Sallmén et al 2003 (+)+ = reduced fecundability, (+) suggestive association
Male pesticide exposure and couples undergoing IVF treatment (Tielemans et
al 1999, 2000)
Reduced fertilization capacity– OR for confirmed exposure 0.38 (0.19-0.78)
– OR for potential exposure 0.54 (0.29-0.99) Improved implantation rate
– OR for high/moderate exposure 3.31 (1.25-8.80)– OR for high(strict) exposure 1.57 (0.33-7.44)
Summary effect?
Male pesticide exposure and spontaneous abortion
Savitz et al 1994, reviewed 14 studies:
elevated RR in >1 study: YES RR > 1.5 YES Evidence from high
quality studies: NOThereafter mainly US studies have shown
associations with spontaneous abortion
Male pesticide exposure and congenital malformations
García 1998, a review on occupational exposure and congenital malformations:17 studies 4 studies showed an association
Conclusion: Inadequate evidence for either establishing a relationship between pesticides exposure in humans and birth defects or for rejecting it.
Male pesticide exposure and congenital malformations
Pesticide applicators in the Red River Valley of Minnesota (Garry et al, 1996, 2002)1996 a register-based study
- excess in birth defects
- seasonal pattern
2002 a cross-sectional interview study- rate of birth defects 7.6% (spring) vs. 3.7% other season
- herbicides: risk of birth defects
- fungisides: determination of sex of the child
Salazar-Garcia et al 2004 (DDT); OR 3.4 (1.2-9.5)
Conclusion: Male pesticide exposure
High exposure associated with reduced semen quality
Inconsistent findings on fecundability Small number of TTP studies The findings of the new studies seem to have
added the evidence that male (or parental) exposure to pesticides is associated with adverse pregnancy outcome
Pesticides and female fertility
Study Association
Fuortes et al 1997 + Greenlee et al 2003 + Curtis et al 1999 + (6 of 13 pesticides)
Abell et al 2000 +
+ = reduced fertility
Summary:Female pesticide exposure and fecundability
There is evidence that female high exposure to pesticides is associated with reduced fecundability
This conclusion is based on small number of studies, however
Female pesticide exposure and adverse pregnancy outcome
Nurminen 1995, and Garcia 1998 reviews: Conclusion: the epidemiologic evidence is
inconclusive as regards the risk of adverse pregnancy outcome
Conclusion: Inadequate evidence for either establishing a relationship between pesticides exposure in humans and birth defects or for rejecting it.
Female exposure to specific pesticides and spontaneous abortion
Exposure/Study Association (OR)Hexachlorobenzene (serum, ng/ml):
Jarrell et al 1998 <1 1.6p=0.113
>14.1 p=0.02
DDT; serum p,p'-DDE measured:
Korrick et al 2001 (each ng/g) 1.13 1.02-1.26
Longnecker et al 2003 (per 60 µg/L)
1.4 1.1-1.6
Pesticides and congenital malformations or foetal death
Female: Exposure assessment Pastore et al 1997 (popul based case-control) + female occup exp Bell et al 2001 (popul based case-control) + residence/application Longnecker et al 2002 (popul based case-c) (+) p,p'-DDE Ribas-Fito et al 2003 (birth cohort, neurodev.) + p,p'-DDE Medina-Carrilo et al 2002 (popul based case-c) + female occup exp Bell et al 2001 (fetal death, popul case-cohort) (+) residence/application Male: Garcia et al 1998 (case-referent) + interview, experts Garry et al 2002 (cross-sectional, popul based) + spring vs. other Regidor et al 2004 (population based) + season Either gender: Kristensen et al 1997(cohort ) + agricultural census Schreinemachers 2003 (population b.) + ecologic
+ = increased risk, (+) suggestive association
Pesticides conclusion: females
Several studies with varying outcomes, pesticides, level of exposure, affected gender, and quality of the study
High exposure seems to be associated with increased risk
Exposure should be restricted through efficient protection
Should pregnant be transferred?
Lead: Pregnancy outcome and fertility
Simultaneous exposure to several metals
Studies around Rönnskär copper smelter
excess of spontaneous abortion, and stillbirths in pregnancies of wives of men exposed to lead, copper, zinc, gold, silver, cadmium, mercury, arsenic, and sulfur dioxide
carry-home exposure to the wives remains a possible alternative explanation
Population-based studies
Rachootin and Olsen 1983
case couples examined or treated for a problem of infertility at Odense University Hospital
questionnaire information on job and exposure
female exposure to lead, mercury, and cadmium were associated with infertility
Maternal lead exposure and spontaneous abortion
B-Pb µmol/L OR 95% CI
A retrospective study among biologically monitored workers:
Taskinen 1988 0.5-3.1 0.8 0.5-1.4Measured within a year of pregnancy:
>1.4 1.9 0.4-9.4
A prospective study (B-Pb measured at gestational age 4-12 w):
Borja-Aburto 0.24-0.48 2.3 --et al. 1999 0.49-0.72 5.4 --
> 0.72 12.2 --
Maternal lead exposure and fecundability
Sallmén et al 1995 (study among women biologically monitored for exposure to lead)
Blood lead FDR 95% CI
not exposed 1.00 reference
<0.5 µmol/l 0.93 0.56-1.57
0.5-0.9 µmol/l 0.84 0.45-1.45
1.0-2.4 µmol/l 0.80 0.42-1.54
Eight most heavily exposed subjects:
1.4-2.4 µmol/l 0.53 0.19-1.52
Maternal lead exposure and cognitive development; prospective studies
Study Mean Blood Lead Effect
Boston 7.37 µg/dl +
Cincinnati 4.6 --->14.1 +
Cleveland5.8 ---> 6.5 -
Port Pirie 14.4->21.2->17.6 +
Sydney 9.1->8.1->12.5 -
Yugoslavia 14.4--->24.3 (+/-)
1 µmol/L = 20.7 µg/dL
Lead and semen quality
Apostoli et al 1997 (a review): Exposure to lead at blood lead 1.9 µmol/L (40
µg/dL) is hazardous for male reproductive function reduced sperm count, volume, and density changed sperm motility and morphology a modest effect on endocrine profile is possible
Viskum et al 1999: The effect is, at least partially, reversible
Studies on birth rates and male exposure to lead
Study PbB level Effect
Selevan et al. 1984 1.2 µmol/l + Coste et al. 1991 1.9 µmol/l - Gennart et al. 1992 2.2 µmol/l + Lin et al. 1996
–duration of exp. >5 years, 2.4 µmol/l + Bonde and Kolstad 1997 1.8 µmol/l -
+ reduced fertility, - no effect
Relative risk (RR) of infertility and male exposure to lead; Sallmén et al 2000
Estimated PbB RR 95% C.I. µmol/L
0.5-0.9 1.27 1.08-1.51
1.0-1.4 1.35 1.12-1.63
1.5-1.9 1.37 1.08-1.72
2.0-2.4 1.50 1.08-2.02
> 2.5 1.90 1.30-2.59
Fecundability Ratio by Male Lead Exposure
0
0,5
1
reference <1.0 1.0-1.4 1.5-1.9 >1.9
Blood lead (µmol/L)
Fec
un
dab
ility
Rat
io
Sallmen et al
J off e et al
shiau et al
Male lead exposure and spontaneous abortion
Study PbB µmol/L OR 95% CI Selevan 1984 1.2 - 1.9 1.5 0.8-3.0
2.0 - 2.9 1.1 0.6-1.9> 3.0 0.9 0.3-2.3
Al-Hakkak 1986 1.8 - 4.6 3.0 p<.01Lindbohm 1991 1.0 - 1.4 1.0 0.6-1.7
1.5 - 1.8 1.3 0.5-3.4> 1.9 1.6 0.6-4.0
Alexander 1996 1.2 - 1.8 1.0 0.6-1.7> 1.9 0.7 0.4-1.5
Male lead exposure and congenital malformations or perinatal death
Study PbB µmol/L OR 95% CI M:Sallmén 1992 > 1.0 2.4 0.9-6.5P:Kristensen 1993 exposed 2.4 1.2-4.9P/M:Alexander 1996 1.2 - 1.8 2.9 0.6-13
> 1.9 2.5 0.5-11
M=malformation studyP=perinatal death study
Solvents: pregnancy outcome and fertility
From a presentation of:
Dr. Marja-Liisa LindbohmFinnish Institute of Occupational Health
Organic solvents
important occupational reproductive hazards: widely used in various fields of industry volatile liquids absorbed via inhalation and through the
skin most solvents traverse the placenta diverse group of compounds
Reproductive effects of solvents
in several human studies exposure related to reduced fertility spontaneous abortions birth defects low birth weight
in some studies exposure related also to menstrual disorders and change in hormone levels pregnancy-induced hypertension neurobehavioral performance reduced semen quality childhood cancer
Maternal exposure to solvents in some occupations and spontaneous abortion
Population
Relative risk (OR)
95% CI
Laboratory workers 1.3 0.9 - 1.9
Laboratory workers: low exposure 1.0 0.6 - 1.7
high exposure 2.3 1.1 - 4.3
Painters (questionnaire data) 2.9 1.0 - 8.8
Painters (register data) 1.4 0.4 - 2.5
Workers monitored for solvents 2.2 1.2 - 4.1
Shoe workers: low exposure 1.6 0.6 - 4.1
high exposure 3.8 1.2 - 11.9
Cumulative percentage of pregnancies by maternal exposure to solvents (Sallmén et al 1995)
0
20
40
60
80
100
1 2 3- 5- 7- 13-24Menstrual cycle
pre
gn
ant,
%
UnexposedLowHigh
Industries and individual solvents related to reduced fertility or adverse pregnancy outcome
Dry cleaning: tetrachloroethylene Semiconductor industry: ethylene glycol
ethers Shoe and leather industry: aliphatic
hydrocarbons, toluene, hexane Laboratory work: toluene, xylene,
chloroform
Ethylene glycol ethers
used in paints, dyes, lacquers, waxes etc.Methoxyethanol embryotoxic and teratogenic in mice and
rats teratogenic effects seen at doses that do
not cause overt maternal toxicityEthoxyethanol induced skeletal defects in rats, multiple
defects in rabbits (inhalation exposure) in rats, impaired performance in behavioral
tests
Spontaneous abortion, fertility and maternal exposure to mixtures containing ethylene glycol ethers in semiconductor industry (Correa et al. 1996, Chen et al 2002)
Outcome Exposure RR/FR 95% CI
Spontaneous abortion: low 1.0 0.6 – 1.7
Correa et al medium 1.4 0.8 – 2.6high 2.8 1.4 – 5.6
Time-to-pregnancy:Correa et al medium 0.8 0.6 – 1.1
high 0.7 0.4 – 1.1Chen et al Exposed 0.59 0.37 –
0.94
Conclusions: Effects of solvent exposure on the reproductive health of women
High exposure to solvents increases the risk of spontaneous abortion and decreases fertility
The findings on birth defects less conclusive, but suggesting adverse effects
Particular solvents associated with adverse effects: ethylene glycol ethers, tetrachloroethylene, toluene
Exposure assessment and recommendation
Assessment of solvent exposure with industrial hygienic measurements or biological monitoring
In some countries the guidelines recommend that solvent exposure should not exceed 10% of the threshold limit value during pregnancy
Reproductive effects have been used as the basis for some TLVs
Exposure to solvents and semen quality or hormone levels
Solvents: reduced sperm quality and decreased implantation rate
Ethylene glycol ethers and 2-bromopropane: reduced sperm count
Styrene and acetone: sperm anomalies Toluene and solvents in general:
decrease of hormone levels
Solvent exposure and seminal characteristics in 225 men who had their first infertility consultation (Oliva et al 2001)
Seminal charateristic OR 95% CI
Seminal volume >3.8 ml 2.4 0.8 – 7.6
Sperm concentration <1x106/ml
2.7 0.9 – 8.3
Sperm output <3x106 2.5 0.8 – 7.9
Sperm motility <50% 3.1 1 – 9.5
Sperm morphology <30% 3.0 1.0 – 9.0
Cumulative percentage of pregnancies by paternal exposure to solvents (Sallmén et al. 1998)
0
20
40
60
80
100
1 2 3- 5- 7- 13-24Menstrual cycle
pre
gn
an
t, %
UnexposedLowHigh
Ethylene glycol ethers and male fertility
Study
FR 95% CI
Samuels et al. 1995
Time-to-pregnancy 1.03 0.70 - 1.51
Correa et al. 1996
Time-to-pregnancy
- Low exposure 0.8 0.6 - 1.1
- Medium exposure 0.9 0.6 - 1.2
Paternal exposure to solvents and spontaneous abortion
Exposure Odds ratio 95% CI
Workers monitored for solvents 2.7 1.3 - 5.6
Styrene (high) 0.7 0.4 - 5.1
Toluene (high) 2.3 1.1 - 4.7
Xylene (high) 1.6 0.8 - 3.2
Dry cleaners (tetrachloroethylene) 0.7 p=0.57
Benzene exposure (high) 1.2 0.7 - 2.1
Ethylene glycol ethers (high) 0.7 0.3 - 1.6
Paternal solvent exposure and pregnancy outcome
Inconsistent findings on the effects of exposure on low birth weight
An excess of birth defects in the children of male painters, but not in the children of other exposed workers
Some evidence for childhood leukemia or nervous system cancers, and paternal exposure to solvents
Evidence inconclusive, although suggestive associations noted
Conclusions: Effects of solvent exposure on the reproductive health of men
Solvent exposure related to reduced sperm quality
Ethylene glycol ethers harmful for male reproductive system
Carbon disulfide related to decreased libido and potency in men
No clear association between solvent exposure and decreased fertility
Male pesticide exposure and spontaneous abortion
Study Association (OR) Arbuckle et al 1999, Ontario Farm Family
Study, phenoxy herbicides<20 weeks of gestation 1.1 0.6-1.9<12 weeks of gestation 2.5 1.0-6.4husband not using protective 5.0 0.7-36.2equipment
Petrelli et al 2000 3.8 1.2-12.0
Crisostomo et al 2002 6.2 1.4-27.9 Salazar-Garcia et al 2004 (DDT)1.5 1.1-2.1
Male/female pesticide exposure and spontaneous abortion
Arbuckle et al 2001Ontario farm population
Timing of exposure / affected gender:
preconceptional early (<12 weeks) abortions(male exposure?)
postconceptional late (12-19 weeks) abortions(female exposure?)
Male pesticide exposure and spontaneous abortion Pesticide applicators in the Red River Valley
of Minnesota (Garry et al, 2002) Fungicides: 1.6-2 -fold increase in risk for
miscarriage/fetal loss Herbicides: increased risk in first-trimester
miscarriage The overall toxicity data suggest a male-
mediated event Also, women engaged in pesticide
application were at risk
Female pesticide exposure and spontaneous abortion
StudyAssociation
Bell et al 2001pesticides showed no strong association with fetal death(ORs from 0.9 to 1.4)
Exposed: lived in 1+ 8 adjacent sq miles fromthe application
Parental pesticide exposure and congenital malformations
Kristensen et al 1997; a study among Norwegian farmers
Exposure to pesticides associated with:spina bifidahydrocephalylimb reductioncryptorchidismhypospadias
Fecundability Density Ratio (FDR) of Pregnancies by Father’s Exposure to Lead; Sallmén et al 2000
Estimated PbB µmol/l N FDR 95% C.I.
0.5-0.9 203 0.92 0.73 - 1.16
1.0-1.4 79 0.89 0.66 - 1.20
1.5-1.8 21 0.58 0.33 - 0.96
> 1.9 23 0.83 0.50 - 1.32
> 1.5 (combined) 44 0.70 0.47 - 1.01
Reproductive effects of some solvents in animal tests
ethoxyethanol: teratogenic and spermatotoxic effects
methyl alcohol: teratogenic effects methyl ethyl ketone: decreased fetal
body weight n-hexane: testicular lesions xylene and white spirit (prenatal
exposure): learning and memory defects
Maternal exposure to solvents and pregnancy outcome: a meta-analysis(McMartin et al. 1998)
559 articles identified; around epid. studies 90
Spontaneous abortions five studies included (n=2899) summary OR=1.25 (95% CI 0.99 – 1.58)
Birth defects five studies included (n=7036) summary OR=1.64 (95% CI 1.16 – 2.30)
Reasons used for the exclusion of (several potentially important) studies criticized
Tetrachloroethylene
used as a dry cleaning agent and degreaser passes across the placenta animal studies:
no clear teratogenic effects signs of fetotoxicity observed in some studies a two-generation study found decrease in litter
size and postnatal survival at 300 ppm propably carcinogenic to humans (2A, IARC)
Maternal exposure to tetrachloroethylene in dry cleaning and spontaneous abortion
Study Odds ratio 95 % CI
Kyyrönen et al. 1989 3.4 1.0 - 11.2
Ahlborg et al. 1990 1.1 0.5 - 2.2
Olsen et al. 1990 2.9 1.0 - 8.4
Doyle et al. 1997 1.6 1.0 - 2.7
Toluene
used in paints, inks, coatings, adhesives, and in the leather, rubber and graphic industries
low birth weight, microcephaly and facial abnormalities in children of women abusing toluene by inhalation during pregnancy
reduced birth weight in prenatally exposed rat pups
effects on cognitive function reported in rats after prenatal exposure
Maternal exposure to toluene and spontaneous abortion or reduced fertility
Population Relative risk 95% CI
Spontaneous abortions OR
Pharmaceutical factory w.
1.9 0.6 – 6.4
Laboratory workers 4.7 1.4 – 15.9
Monitored workers 1.4 0.4 – 4.9
*Audio speaker factory w.
2.8 1.3 – 5.9
Reduced fertility (ttp) FDR
Monitored workers 0.71 0.40-1.26
*Printing industry workers
0.47 0.29-0.77
Maternal exposure to solvents and oral clefts
Study Odds ratio 95 % CI
Holmberg et al. 1982 14 exp. cases, 4 exp.
controls
p<0.05
Cordier et al. 1992 7.9 1.8 - 44.9
Laumon et al. 1996 1.6 1.0 - 2.5
Cordier et al. 1997 (glycol ethers)
1.9 1.0 - 3.5
Methodological issues in epidemiologic studies on solvents
response rates satisfactory in most studies confounding usually, but not always controlled for outcome data mainly from the medical records
data on exposure usually based on workers’ own reports - underreporting ?
in some studies exposure assessed by experts exposure to mixture of solvents common
small sample size in studies on birth defects and individual solvents
Reproductive endocrine effects in women with fuel/solvent exposure (Reutman et al 2002)
Outcome: urinary endocrine markers related to nonconceptive menstrual cycles (N=63)
Exposure assessment: levels of aliphatic and aromatic hydrocarbons (HCs) in exhaled breath
Result: preovulatory luteinizing hormone level significantly lower among women who had higher internal doses of aliphatic HCs
Conclusion: compounds in fuel and some solvents may act as reproductive endocrine disruptors
Genetic susceptibility to benzene and shortened gestation (Wang et al 2000)
Aim: examine whether the association between exposure and outcome is modified by two susceptibility genes CYP1A1 and GSTT1 responsible for detoxification of solvents (542 mothers)
Results: benzene exposure associated with a decrease in
mean gestational age when stratified by the maternal CYP1A1
genotype, the decrease was significantly greater for the AA group than for the AA/aa group
Provide evidence of gene-environment interaction
Carbon disulfide exposure and the prevalence of sexual complaints
Sexualcomplaint
Non-exposed
Lowexposure
Highexposure
p-value
Decreasedlibido
13.9% 13.6% 37.2% .005
Impotence 3.8% 9.1% 20.0% .02
Vanhoorne et al. 1994
Solvent exposure and count of motile sperm (Cherry et al 2001)
A case-referent study of 656 infertility patients
Aim: to examine whether cases with low motile sperm count (<12x106ml) were more likely than referents to have had exposure to solvents
Exposure assessment: job exposure matrix of previous studies on solvent exposure
Results: OR 2.1 (95% CI 1.2-3.4) for moderate exposure OR 3.8 (95% CI 1.4-10.6) for high exposure