Priority Substances List Assessment Report- 1,3-Butadiene

3.0 Assessment of "Toxic" Under CEPA 1999 (Continued)

3.3 CEPA 1999 64(c): Human health

3.3.5 Uncertainties and degree of confidence in human health risk characterization

There is a high degree of certainty that butadiene is being released to ambient air in Canada in significant amounts in vehicular exhaust. There is a moderate degree of certainty that exhaust emissions of butadiene are lower in wellmaintained vehicles equipped with catalytic converters than in older non-catalyst-equipped vehicles, and that evaporative emissions during refuelling and vehicle operation contribute less to concentrations of butadiene in ambient air than do emissions in vehicular exhaust.

There is a moderate degree of certainty that butadiene is not being released to the Canadian environment in significant amounts from industrial activities in Canada, as only a single major point source (i.e., in Sarnia, Ontario) of discharge to the atmosphere has been identified. Although there is some uncertainty that the available measurements of butadiene in samples taken over a few days in the vicinity of this source are representative of population exposure over the long term, since the samples were taken at distances of up to a few kilometres from the source, there is a moderate degree of certainty that a segment of the population would be exposed to the measured concentrations. There is a high degree of certainty that populations in rural areas are exposed to lower concentrations of butadiene in ambient air than are communities in more densely populated areas.

Available data on concentrations of butadiene in ambient air in Canada are quite extensive. A large proportion of the numerous samples from several sampling sites across the country contained concentrations of butadiene above the level of detection. Therefore, there is a high degree of certainty in the estimations of exposure to butadiene via ambient air.

The most limiting aspect of the exposure assessment is the lack of sufficient data on the concentrations of butadiene in indoor air. This is an important shortcoming, since humans spend significantly greater time in indoor environments than outdoors. In the absence of indoor sources, it is reasonably certain that concentrations of butadiene in indoor environments are similar to the concentrations in the local ambient air.

Higher concentrations of butadiene have been measured in indoor air where ETS was known to be present. However, the data on concentrations of butadiene in ETS-contaminated indoor air are highly variable and are not sufficient to reasonably define the range of mean concentrations. Nevertheless, there is a high degree of certainty that non-smokers spending a considerable proportion of their time in indoor environments where ETS is present are exposed to higher concentrations of butadiene than are non-smokers who are not exposed to ETS. There is a high degree of certainty that smokers are exposed to higher concentrations of butadiene and have significantly higher daily intakes than do non-smokers. However, there are no reliable, recent data on the content of butadiene in the mainstream smoke of Canadian cigarettes.

There is somewhat less certainty that butadiene monomer is not released in detectable amounts from consumer products (e.g., synthetic materials) incorporating this compound in their production. Although there may be contributions to indoor concentrations of butadiene from certain cooking activities, the data are not sufficient to identify specific sources or activities or to identify a range of emissions of butadiene during cooking.

Although data on levels of butadiene in foodstuffs are scarce, based on the physical and chemical properties of the substance and the fact that it is released primarily to ambient air (where it is likely to remain without partitioning to other media), there is a reasonable degree of certainty that food does not represent a major source of exposure. Similarly, although the database for concentrations of butadiene in drinking water is limited, there is a reasonable degree of certainty that drinking water is not an important source of exposure for the general public in Canada, based on the volatility and release patterns of the compound.

There is some degree of uncertainty that the weight of epidemiological evidence for the association between butadiene and leukemia satisfies criteria for causality. In particular, the need for coherence is seemingly not addressed, since the observed increase in mortality due to leukemia in styrene-butadiene rubber workers was not observed in the cohorts of monomer workers (although there was some evidence of an association with other forms of lymphohematopoietic cancer, particularly in short-term workers). This may be related to the nature of exposure to both butadiene and other substances in these two industries. However, in view of the overwhelming evidence of carcinogenicity and genotoxicity in experimental animals, available information on species differences in sensitivity likely being related to differences in metabolism and the potential for considerable interindividual variability in metabolism to putatively toxic metabolites in the human population, along with the limited evidence of genotoxicity in occupationally exposed populations, there is a high degree of confidence that butadiene is likely to be carcinogenic in humans. Based on the extensive database on the genotoxicity of butadiene and its principal metabolites both in vitro and in vivo in both somatic and germ cells, confidence that butadiene induces tumours (and possibly other effects) through direct interaction with genetic material is high.

Although the assessment of the exposure of the critical cohort of workers is likely one of the most comprehensive published to date, there is also uncertainty in the estimates of carcinogenic potency derived on the basis of this study, due primarily to the fact that the estimates of exposure are based on only a limited number of actual historical monitoring data.⁹ For example, when the exposure of workers at one plant was reexamined, there were two- to threefold changes in the estimates for several job groups (with a 10-fold increase for one job group). In addition, with the exception of incorporating exposure to styrene as a stratification variable in the analyses, potential interactions between various occupational exposures could not be taken into account in the derivation of the carcinogenic potency based on the observations in this cohort. It has also been demonstrated that genetic polymorphism for several of the enzymes involved in metabolism of butadiene affects sensitivity to toxic effects induced by the substance. Also, since information on genotype for the relevant enzymes was not available for this large cohort and only a small amount of information on the distribution in the general population has been identified, it is not possible to determine how representative the study cohort is of the genetic susceptibility to butadiene of the general public.

With respect to the quantitation of exposure-response and derivation of potency estimates based on the epidemiological data, the inability of any of the models to consistently predict leukemia rates in the validation study contributes to additional uncertainty. In addition, the small number of leukemia cases being modelled contributes to model instability. However, the fact that the range of potency estimates for the four models is narrow (i.e., 1.4-4.3 mg/m³) increases the confidence in the calculated potencies.

In view of the likely variability in metabolism of butadiene across the human population related to genetic polymorphism for relevant enzymes, estimates of carcinogenic potency as well as benchmark concentrations for non-cancer effects based on studies in mice are considered justifiably conservative. However, because of the high mortality in the study in mice in which exposure-response could best be characterized and the limitations in the study in rats (high mortality at the higher of only two widely spaced exposure levels), there is a moderate degree of uncertainty in estimates of carcinogenic potency derived on the basis of investigations in experimental animals. It is noteworthy that if the calculated margins between exposure and carcinogenic potency presented above that serve as a basis for prioritization of options to reduce exposure were derived on the basis of the 95% LCLs of the TC₀₅s for tumours in mice, the values would differ by only 1.4- to 3.3-fold (i.e., within the same order of magnitude) from those calculated on the basis of the point estimates; similarly, use of the 95% LCLs of the TC₀₅s for tumours in rats would result in a 1.1- to 6.4-fold difference in the margins between exposure and potency. Also, it should be noted that, although these margins and measures of risk (EPIs) presented above were based on comparison of the 95th percentile of the exposure data for each scenario, use of the median concentration (i.e., the 50th percentile) and either the point estimates of carcinogenicity or the associated 95% LCLs would result in a fivefold difference in the resulting values for the general population and a 10-fold difference in values for those in an area influenced by a point source. However, for almost all exposure scenarios, the priority for investigation of options to reduce exposure would remain moderate to high.

There is uncertainty about the relevance of the ovarian atrophy observed in mice to humans, based on lack of data on the relative role of butadiene in the etiology of these lesions. As a result, quantitative measures of dose- response developed on this basis must necessarily be interpreted with caution. In addition, the BMC₀₅ presented above was based on inclusion of ovarian atrophy of all severities, including "minimal" severity, the biological significance of which is unclear. If only lesions of moderate or marked severity are considered, the resulting BMC₀₅ and hence the calculated margin between exposure and effect level and EPIs would differ by about fivefold. (N.B.: Use of the 95% LCLs of the BMC₀₅s for atrophy of all severities or of only moderate or marked severity would result in only a 1.5- or 3-fold difference in the measure of risk.) However, in view of the weight of evidence of causality for the association between butadiene and these effects in mice and the relatively low value for the measure of dose-response compared with that for other types of effects, additional investigation in this area is deemed to be of high priority.

3.4 Conclusions

CEPA 1999 64(a):

Based on analyses of the worst-case situations that could likely be encountered in Canada, risk quotients for water, air and soil are less than 1. The environmental risks associated with concentrations of butadiene likely to be found in Canada therefore appear to be low. Based on available data, it has been concluded that it is unlikely that butadiene is entering or may enter the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity. Therefore, butadiene is not considered to be "toxic" as defined in Paragraph 64(a) of CEPA 1999.

CEPA 1999 64(b):

Butadiene is not involved in depletion of stratospheric ozone and likely does not contribute significantly to climate change. Based on its abundance and reactivity in air, it plays a role, along with other reactive volatile organic chemicals, in tropospheric ozone formation. Therefore, based on available data, it has been concluded that butadiene is entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger to the environment on which life depends. Therefore, butadiene is considered "toxic" as defined in Paragraph 64(b) of CEPA 1999.

CEPA 1999 64(c):

Available data support a plausible mode of action for induction of tumours (and possibly related reproductive effects, although data are inconclusive in this regard) by butadiene involving direct interaction with genetic material. On this basis, butadiene is considered to be "toxic" as defined in Paragraph 64(c) of CEPA 1999. This approach is consistent with the objective that exposure to compounds where induction of cancer (and possibly other effects) through direct interaction with genetic material is likely be reduced wherever possible and obviates the need to establish an arbitrary "de minimis" level of risk for the determination of "toxic" under CEPA 1999. Based on comparison of estimates of exposure with the potency for leukemia in humans and cancer and noncancer effects in experimental animals, and taking into consideration the degree of confidence in the database upon which the quantitative measures of toxicity were based, the overall priority for investigation of options to reduce exposure to butadiene in the general environment in Canada, based solely on potential adverse health effects, is considered to be moderate to high.

Overall conclusion:

Based on critical assessment of relevant information, butadiene is considered to be "toxic" as defined in Section 64 of CEPA 1999.

3.5 Considerations for follow-up (further action)

Butadiene contributes to the photochemical formation of ground-level ozone. It is recommended that key sources of butadiene be addressed, therefore, as part of management plans for volatile organic chemicals that contribute to the formation of ground-level ozone.

Based on comparison of estimates of exposure for the general population with the tumorigenic potency, the priority to investigate options to reduce exposure of butadiene in ambient air in the vicinity of the identified point sources is considered to be high while that from more dispersive non-point sources (identified herein primarily as transportation) is considered to be moderate to high. Investigation of concentrations and potential sources of butadiene in indoor air may also be warranted.

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⁹ Although it has not been possible to quantitatively characterize uncertainty regarding these estimates of exposure and the impact of this uncertainty upon the estimates of carcinogenic potency, data being collected currently may permit a more quantitative characterization in future (Lynch, 1998).