A Comprehensive Evaluation of the Potential Health Risks Associated with Occupational and...

Harvard Center for Risk Analysis

A Comprehensive Evaluation of the Potential Health Risks Associated with Occupational

and Environmental Exposure to Styrene

Joshua CohenHarvard Center for Risk AnalysisHarvard School of Public Health

December, 2002


Expert Panel

• Commissioned by the Styrene Information and Research Center (trade association) in 1999

• Panel members– Gary Carlson -- Purdue University– David Coggon -- University of Southampton (UK)– Elizabeth Delzell -- University of Alabama– Helmut Greim -- GSF-Institute of Toxicology– Daniel Krewski -- University of Ottawa– Michele Medinsky– Richard Monson -- Harvard School of Public Health– Dennis Paustenbach -- Exponent– Barbara Petersen -- Novigen Sciences– Stephen Rappaport -- University of North Carolina– Lorenz Rhomberg -- Gradient Corporation– P. Barry Ryan -- Rollins School of Public Health, Emory University


Report Staff

• Harvard Center for Risk Analysis– Joshua Cohen– John Graham– Kim Thompson

• Health Risk Strategies (Washington, DC)– Gail Charnley


Styrene UseTotal Production -- 10 Billion Pounds per Year

Resin Category Estimated percentof total resin

production (%)

Typical fabrication products

Polystyrene (PS) 50 Building construction, cups, plates, eggcartons, cassettes, packaging, dairycontainers, toys

Styrene butadiene rubber(SBR)

15 Tires, automotive parts

Unsaturated polyesterresins (UPR)

12 Boats, tubs, shower stalls, spas, hot tubs,cultured marble products

Styrene butadiene latexes(SBL)

11 Carpet and upholstery backing, papercoatings

Acrylonitrile-butadiene-styrene (ABS)

10 Appliances, transportation, businessmachines, construction materials

Styrene-acrylonitrile(SAN)

1 Appliances, automotive materials,housewares, battery casings, packaging


General Population Exposure:Inhalation

Exposure Scenario MaximumAnnualAverage

LifetimeAverage

Typical ambient exposure 1 ppb 1 ppb

High-end ambient exposure 5 ppb 5 ppb

Exposure to styrene from smoking 6 ppb < 6 ppb

Living 100 meters from a 100,000 pound per year emissionfacility (high exposure scenario, 95th percentile individual)

12 ppb 2.8 ppb

Living at the point of greatest exposure in the vicinity of a 1million pound per year emission facility (high exposurescenario, 95th percentile individual)

700 ppb 219 ppb


General Population Exposure:Food

• Naturally occurring styrene in food – e.g., cinnamon, coffee, beer– Total intake (assuming 3 kg food/day) -- 0.6 ug/day

• Styrene leached from food packaging and disposable food contact articles -- 9 ug/day

• Total -- 10 ug/day, or around 0.2 ug/kg-day for a 70 kg adult


General Population Exposure:Water

• Minimal -- Styrene does not persist in water due to its biodegradation and volatility


Occupational Exposure:Inhalation

Lifetime AverageExposure(Cancer)

8-hr TWA Exposure(Non-cancer)

Industry segments other than reinforcedplastics

20 ppb 0.2 to 3.5 ppm

Highly exposed workers in the reinforcedplastics industry (omitting potential impact ofoccupational exposure to styrene oxide)

1,000 ppb 37 ppm

Highly exposed workers in the reinforcedplastics industry (including potential impactof occupational exposure to styrene oxide)

2,400 ppb 37 ppm


ToxicologyRats Exposed to Styrene

• Gavage studies negative

• Inhalation studies– Statistically positive for mammary tumors (Jersey et al., 1978),

benign mammary tumors and all mammary tumors (Conti et al., 1988), testicular tumors (Cruzan, 1998)

– Dose-response relationships not monotonic and not consistent across studies

– Panel concluded relationships were not causal


ToxicologyMice Exposed to Styrene

• Gavage studies -- some positive for lung tumors, but relationship did not appear to be causal

• Inhalation studies– Cruzan et al. (2001) positive for lung tumors– Panel concluded relationship is causal -- tumor incidence

statistically elevated at 40, 80, and 160 ppm


ToxicologyMice and Rats Exposed to Styrene Oxide

• Gavage studies -- positive at site of entry

• Dermal studies– Negative


Noncancer

• Central nervous system depression has been observed in workers at exposure above 100 ppm

• Ototoxicity (hearing loss) has observed at 35 ppm and 25 ppm, but those occupational studies were poorly controlled

• Styrene does not appear to have endocrine modulating effects

• Reproductive and developmental toxicity have been observed in animal studies at high levels of exposure

• Panel’s comparison dose – 50 ppm– Subclinical impairment of color vision


Reinforced Plastics - EuropeKolstad et al. (1993)

Cohort study – 53,731 M and 10,793 W from 552 companies in Denmark

Kolstad et al. (1994)

Cohort study – Males from Kolstad et al. (1993).N = 53,720.

Kolstad et al. (1995)

Cohort study – Males from Kolstad et al. (1994) working in 460 companies with “known” exposure status (i.e., excluding 82 companies). N = 50,903

Coggon et al. (1987)

Cohort study – 7,949 M and W employed from 1947 to 1984 in 8 British plants

Workers from Finland, Italy, Norway, Sweden, and 51 more plants in the UK not included in Coggon et al. (1987)

N = 15,863 M and W classified by Kolstad as “highly exposed”

Kogevinas et al. (1993, 1994)

Cohort study – N = 40, 683 M and W.


Conclusions:European Reinforced Plastics

• Findings generally negative

• Sources of bias towards the null– Inadequate characterization of exposure, with exposures from

earlier periods (when they were likely to be higher) only roughly estimated

– Inaccurate cancer diagnosis

• Where elevated cancer rates were reported, they were inconsistent with findings from other industry segments


Reinforced Plastics – North America

Wong et al. (1990, 1994).

Cohort study – 15,826 (11,958 M and 3,868 F) employed at least 6 mos at 30 plants

Okun et al. (1985).

Cohort study – 5,021 (4,519 M and 682 F) employed at 2 Washington State boatbuilding facilities.

Positive findings for lung cancer


Conclusions:American Reinforced Plastics

• Wong study findings of elevated lung cancer risk– Findings confined to workers with less cumulative exposure to styrene

and shorter duration of employment– Among the cohort as a whole, and especially among short duration

workers, other diseases linked to life style elevated (cancer of the cervix, ischemic heart disease, etc.)

– No elevation in lung cancer risk in European reinforced plastics industry

• Panel concluded elevation reflects confounding

• Other elevated rates reported by Wong were not associated with cumulative exposure


Styrene Butadiene Industry

• Plants built during WWII and the 1950’s in North America – 15 plants built in the U.S. during WWII – 1 plant built in Canada during WWII– 1 plant built in the U.S. during the 1950’

• Plants still operating in 1977: 10, including the Canadian plant and the plant built during the 1950’s


Styrene – Butadiene Industry (continued)Meinhardt et al. (1982)

Cohort study – 2 plants in Texas not included in Matanoski et al. (1990)

Matanoski et al. (1990)

Cohort study – 8 of the plants still operating in 1977, excluding the 2 studied by Meinhardt et al. (1982). Included with 1+ years of experience workers hired before 1/1/77. Canadian workers restricted to individuals 45 years of age or 10+ years experience.

Delzell et al. (1996)Sathiakumar et al. (1998)

Cohort study based on 7 of the 8 plants in Matanoski et al. (1990) and both plants from Meinhardt et al. (1982). Included workers with 1 year work experience by 1/1/92.

Santos-Burgoa et al. (1992)Matanoski et al. (1993)

Case-control – 59 lymphohematopoietic cancers and 193 controls

Macaluso et al. (1996)

Cohort study based on all but 2 of the plants in Delzell et al. (1996)

Matanoski et al. (1997)

Case-control – 58 lymphohematopoietic cancers and 1242 controls

Positive findings


Epidemiology Findings

• Number of expected and observed cancers are small and hence estimates are uncertain

• Confounding– Styrene-butadiene industry – Workers exposed to butadiene,

which may explain the excess in observed leukemias

• Leukemias not elevated consistently in the reinforced plastics industry, where exposure to styrene is much greater


Epidemiology Findings(Continued)

• Confounding– Styrene-butadiene industry – Workers exposed to butadiene,

which may explain the excess in observed leukemias


Epidemiology -- Conclusions

• Negative study findings are not statistically inconsistent with the risk estimates from the positive Cruzan et al. (2001) study– 95% confidence interval for all neoplasms among highly exposed

reinforced plastics workers from both the Wong et al. and Kogevinas et al. studies (average exposure 300 ppm-yrs): 90-109

– Relative risk among these workers predicted using the (adjusted) dose-response relationship from Cruzan et al. (2001) is 1.07


Mode of Action

• Styrene exposure leads to adduct formation– Occupational exposure to styrene in the reinforced plastics

industry results in persistent O6 adducts– No evidence that these adducts are associated with adverse health

effects

• Styrene oxide exposure causes DNA strand breaks, but these are quickly repaired.


Mode of Action – ContinuedCytogenetic Activity

• In vitro studies – Positive for both styrene and styrene oxide – Results are sensitive to the simulated metabolic environment– Implications for human health unclear

• Animal studies– Styrene and styrene oxide are genotoxic only at very high exposure levels

• In humans– Chromosomal abnormalities – Evidence compelling at occupational

exposure levels, with dose responses both within and across studies– Sister chromatid exchanges –most studies negative– Micronuclei -- No association with styrene exposure


Mutagenic Effects

• Styrene oxide causes mutations in the Ames Salmonella assay, but results in animals and humans are less clear cut


Key QuestionAre Humans Like Rats or Mice

• Panel concluded that only one styrene exposure study was positive– Cruzan et al. (1998) -- Lung tumors elevated at 40 ppm

• Same methodology applied to rats (Cruzan et al., 2001)– Results negative at 1,000 ppm !


Cruzan et al. (2001) - Male Mice

0%

10%

20%

30%

40%

50%

60%

70%

80%

0 20 40 80 160

Styrene Dose (ppm)

Frac

tion

of A

nim

als

with

Tum

ors

Benign Malignant Benign or Malignant


Cruzan et al. (2001) - Female Mice

Benign Malignant Benign or Malignant

0%

10%

20%

30%

40%

50%

60%

0 20 40 80 160

Styrene Dose (ppm)

Frac

tion

of A

nim

als

with

Tum

ors


Rats -- Cruzan et al. 1998Pulmonary Adenomas

Exposure Concentration (ppm)Gender 0 50 200 500 1000

Male (N) (60) (60) (60) (54) (52)% Positive 0.0% 0.0% 1.7% 0.0% 0.0%

Female (N) (60) (60) (60) (60) (60)% Positive 0.0% 1.7% 0.0% 0.0% 0.0%


The Metabolism of Styrene

Styrene

CytochromeP-450

Styrene Oxide

PhenylethyleneGlycol

Epoxide Hydrolase

Furthermetabolism and

excretion

+ glutathione(GSH)

x-Phenyl-2-hydroxy-

ethylmercapturicacid


Factors That May Predispose Mice to the Development of Tumors

Concentration of SO in the Blood of Mice and Rats Following Exposure to Airborne Styrene

0

1

2

3

4

5

6

0 500 1000 1500

Airborne Styrene (ppm)

SO in

Blo

od (u

g/L)

Mice - Kessler et al.,1992

Mice - Morgan et al.,1993b

Mice - Cruzan et al.,submitted

Rats - Kessler et al.(1992)

Rats - Cruzan et al.,1998


Factors That May Predispose Mice to the Development of Tumors

Ratio of R- to S-Enantiomer Styrene Oxide Produced as theResult of Pulmonary and Hepatic Metabolism

Reference Species Ratio ofR-SO to S-SOStyrene OxideLung Liver

Carlson (1997a) Mouse 2.57 1.682.60 1.62

Carlson (1997b) Mouse 2.36a 1.62a

1.68b 1.78b

Carlson et al. (1998) Mouse 2.38 1.28

Hynes et al. (1999) Rat 0.52c 0.57c

Mouse 2.40c 1.18c


In Terms of Pharmacokinetics, Humans are more like Rats

• SO levels in the blood of humans are “5 - 20 times lower than the corresponding values in rodents” (IARC, 1994, p. 274).

• The ratio of R-SO to S-SO production (Carlson et al., 2000):– Lungs -- 1.15– Liver -- 0.72

• Note -- Human measurements are relatively sparse and hence not as reliable as measurements in rodents

• Does pharmacokinetics explain why mice are more susceptible to the development of lung tumors than rats following styrene exposure?


Findings• Calibration of model to Cruzan et al. (1998) and Cruzan et al.

(submitted):

– Mouse pulmonary SO < rat pulmonary SO– Reverse of what is expected!

• Calibration of model to Kessler et al. (in prep), Morgan et al, (1993b), and Kessler et al., 1992:

– Mouse pulmonary SO 5X greater than rat pulmonary SO at styrene concentrations up to 300 ppm

– Mouse pulmonary SO 25X greater than rat pulmonary SO at styrene concentrations above 300 ppm


Findings(Continued)

Mouse Parameters Consistent withKessler et al. (in prep), Morgan etal, (1993b), and Kessler et al., 1992

Mouse Parameters Consistent withCruzan et al. (submitted)

ExposureConcentration

(ppm)

MouseLung SO

(ppm)

RatLung SO

(ppm)

Ratio –Mouse to

Rat

MouseLung SO

(ppm)

RatLung SO

(ppm)

Ratio –Mouse to

Rat20 3.9 1́0-4 7.7 1́0-5 5.0 1.9 1́0-5 7.7 1́0-5 0.2440 6.9 1́0-4 1.4 1́0-4 4.9 3.6 1́0-5 1.4 1́0-4 0.2580 1.1 1́0-3 2.4 1́0-4 4.6 6.5 1́0-5 2.4 1́0-4 0.27

160 1.7 1́0-3 3.8 1́0-4 4.5 1.1 1́0-4 3.8 1́0-4 0.28200 1.9 1́0-3 4.3 1́0-4 4.5 1.2 1́0-4 4.3 1́0-4 0.29300 2.5 1́0-3 5.2 1́0-4 4.8 1.5 1́0-4 5.2 1́0-4 0.29400 4.3 1́0-3 6.0 1́0-4 7.2 1.7 1́0-4 6.0 1́0-4 0.28500 7.9 1́0-3 6.6 1́0-4 11.9 1.8 1́0-4 6.6 1́0-4 0.27600 1.1E-2 7.2 1́0-4 15.3 1.9 1́0-4 7.2 1́0-4 0.26700 1.4 1́0-2 7.9 1́0-4 17.5 2.0 1́0-4 7.9 1́0-4 0.25800 1.7 1́0-2 8.6 1́0-4 19.8 2.1 1́0-4 8.6 1́0-4 0.24900 2.1 1́0-2 9.3 1́0-4 22.2 2.1 1́0-4 9.3 1́0-4 0.23

1,000 2.4 1́0-2 1.0 1́0-3 24.2 2.2 1́0-4 1.0 1́0-3 0.22

Panel Model Predictions – Concentration of Styrene Oxide in the Lungs of Rats and Mice:

Exposure Six Hours per Day, Five Days per Week


Findings(Continued)

• Glutathione depletion in the lungs of mice notably exceeds glutathione depletion in the lungs of rats, but it is notable only at concentrations greater than those at which mice first develop tumors

• R-SO concentrations in the lungs of mice are not substantially greater than corresponding concentrations in mice


Post Script

• Sarangapani et al. developed a model that can be used to estimate SO concentrations on a finer scale (i.e. inside and near the cells that produce SO in the lung)

• They found a greater difference in delivered dose between mice and rats than we found


Post Script• Mice exposed to 20 ppm styrene had a 21% increase in lung

tumor incidence above controls (not significant). Rats exposed to 1000 ppm had no increase in lung tumors above controls.

• Delivered dose in mice exposed to 20 ppm increase was only 2x higher than in rats exposed to 1000 ppm

• Substantial uncertainty - Many other sets of assumptions would produce higher delivered dose values for rats than mice at those exposures

• Although pharmacokinetics play a role in sensitivity of mice to styrene, other factors must also be at play

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