Toxicological risk assessment in the courtroom: are available methodologies suitable for evaluating toxic tort and product liability claims?

Courts are increasingly faced with the need to resolve claims by individuals that they have been injured by chemical exposures or that they have been put at sufficient risk by such exposures that their health status must be monitored to ensure the earliest possible detection of developing injuries or diseases. This paper offers the view that the principles and methods developed and applied by toxicologists, epidemiologists, and risk assessors to support regulatory and public health decision-making are inadequate to evaluate the types of claims that courts are called upon to resolve in such cases. No well-described alternative methodology appears to be available, and as a result, courts are exposed to a wide range of expert opinions based on diverse, conflicting, and sometimes baseless methodologies. It is suggested that there may be value in an effort by the community of professionals in toxicology, epidemiology, and risk assessment to devote attention to the types of data and scientific methodologies that might be appropriate for evaluating the technical questions that such claims provoke. Such an effort might assist trial judges in the role they have been assigned in the Supreme Court's 1993 Daubert decision, wherein they are asked to make a preliminary assessment of the admissibility of the scientific methodologies relied upon by various experts. Such an assessment, if based on an understanding of the types of data and methodologies suitable for evaluating claims of injury, offers the possibility of limiting the range of expert opinion that ultimately is heard in courtrooms to that which conforms to scientifically valid standards.

Leukemia risk associated with benzene exposure in the pliofilm cohort: I. Mortality update and exposure distribution.

The National Institute of Occupational Safety and Health (NIOSH) recently completed a vital status update adding 6 years of observation on the rubber workers known as the Pliofilm cohort. Using traditional standardized mortality ratio (SMR) analysis, we investigate the impact of the additional information gathered in the NIOSH update. We also compare the effect of using three sets of job-, plant-, and year-specific exposure estimates on the evaluation of benzene's leukemogenicity. The lack of any additional cases of multiple myeloma does not support trends toward elevated risks for this endpoint (as had been observed earlier), and there is no indication of increased incidences of solid tumors (as predicted by animal studies). Qualitatively, which exposure estimates are used does not alter the conclusions. The data added in the update did not greatly modify the estimated relative risk of leukemia associated with benzene exposure, but did confirm previous findings that occupational exposure to high concentrations had leukemogenic potential. The fact that leukemia has not been observed in any individual who started employment in Pliofilm production after 1950 suggests that the observed leukemia cases could be a response to very high levels of benzene exposure that occurred during the early years of this manufacturing process.

Leukemia risk associated with benzene exposure in the pliofilm cohort. II. Risk estimates.

The detailed work histories of the individual workers composing the Pliofilm cohort represent a unique resource for estimating the dose-response for leukemia that may follow occupational exposure to benzene. In this paper, we report the results of analyzing the updated Pliofilm cohort using the proportional hazards model, a more sophisticated technique that uses more of the available exposure data than the conditional logistic model used by Rinsky et al. The more rigorously defined exposure estimates derived by Paustenbach et al. are consistent with those of Crump and Allen in giving estimates of the slope of the leukemogenic dose-response that are not as steep as the slope resulting from the exposure estimates of Rinsky et al. We consider estimates of 0.3-0.5 additional leukemia deaths per thousand workers with 45 ppm-years of cumulative benzene exposure to be the best estimates currently available of leukemia risk from occupational exposure to benzene. These risks were estimated in the proportional hazards model when the exposure estimates of Crump and Allen or of Paustenbach et al. were used to derive a cumulative concentration-by-time metric.

Risk assessment, the environment, and public health.

Risks to human health arise from the environment in diverse ways and from many sources. Although there are many social forces to be considered when efforts are made to protect human health, it would seem that public health resources should be devoted to reducing risks arising from the environment in at least rough proportion to the toll they take on human health. Risk assessment, properly, conceived and practiced, is the appropriate tool for assigning risks their rightful order and should be a principal component of public health programs everywhere. The successful application of risk assessments to such goals depends on the developments of a broader view of its nature and content than has been customarily adopted.

Assessment of the potential risk to workers from exposure to 1,3-butadiene.

The available epidemiologic data provide equivocal evidence that 1,3-butadiene is carcinogenic in humans; some available studies suggest that the lymphopoietic system is a target, but there are inconsistencies among studies in the types of tumors associated with 1,3-butadiene exposure, and there is no evidence of a relationship between length of exposure and cancer risk, as one might expect if there was a true causal relationship between 1,3-butadiene exposure and cancer risk. The available chronic animal studies, however, show an increase in tumor incidence associated with exposure to high concentrations of 1,3-butadiene. In addition to the general uncertainty of the relevance of animal data to humans, there are several additional reasons why the National Toxicology Program's mouse study may not be appropriate for assessing possible human risks. These include: a) the possible involvement of a species-specific tumor virus (MuLV) in the response in mice; b) apparent differences between mice and humans in the rate of metabolism of 1,3-butadiene to reactive epoxides that may be proximate carcinogens; c) use of high dose levels that caused excess early mortality; and d) exposure of animals to 1,3-butadiene for only about half their lifetime. While recognizing the uncertainty in using the available animal data for risk assessment, we have performed low-dose extrapolation of the data to examine the implications of the data if humans were as sensitive as rats or mice to 1,3-butadiene, and to examine how the predictions of the animal data compare to that observed in the epidemiologic studies. With the mouse data, because the study was of less than lifetime duration, we have used the Hartley-Sielken time-to-tumor model to permit estimation of lifetime risk from the less than lifetime exposure of the study. With the rat data, we have used three plausible models for assessing low-dose risk: the multistage model, the Weibull model, and the Mantel-Bryan probit model. With both the rat and mouse data, we used information on how much 1,3-butadiene is retained by animals exposed to various concentrations of the chemical. This improves the accuracy of the low-dose extrapolation. When extrapolated to low-dose levels, mice appear to be at greater risk (by a factor of 5-fold to 40-fold) than rats. Some of this difference (a factor 3-fold to 5-fold) may be due to the faster rate of metabolism of 1,3-butadiene to, and higher blood levels of, epoxide derivatives in mice than in rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Some issues in risk assessment for agricultural chemicals.

Risk assessment is now a significant feature of most environmental risk management programs, in both industry and government. The purpose of this paper is to describe the elements of risk assessment, their strengths and limitations, and their relationship to other activities, including research and risk management. Risk assessment issues to be examined are those especially important to the agricultural community, including problems of high-risk subpopulations, exposure through unauthorized pathways (e.g., those resulting from groundwater contamination or pesticide misuse), and inadequacies in toxicity and residue data bases.

Review and update of leukemia risk potentially associated with occupational exposure to benzene.

Since the 1980 U.S. Supreme Court decision on the Occupational Safety and Health Administration's (OSHA) proposal to lower the occupational benzene standard from 10 ppm to 1 ppm, numerous quantitative assessments of the leukemia risk of benzene exposure have been prepared. The primary difference between these risk assessments has been in the way in which benzene exposure has been estimated and in the models applied to describe the dose-response relationship. The more recent assessments, in attempting to estimate benzene exposures on an individual basis, and in applying models which make maximal use of the available data points, represent a substantial improvement over earlier assessments. In this paper, we will review the available risk assessments and the data upon which they are based and will present our own assessment, which builds on prior efforts. Our reevaluation of the underlying data on the cohort that we judged to be most suitable for quantitative risk analysis suggested that past assessments may have overestimated risk by a factor of 3 to 24. In addition, we will present some recently made available data of relevance to the benzene exposure histories of cohort of concern. These data provide additional suggestion that the total benzene exposure of certain members of this cohort has likely been seriously underestimated, the extent to which remains to be determined. Further analysis of these data and pursuit of additional sources to improve the characterization of the benzene exposure of this cohort appear to be warranted in order to define more precisely the benzene-leukemia dose-response relationship.

Review of interspecies risk comparisons.

Use of laboratory animal data to make quantitative predictions of the risks of toxic effects in humans assumes that a relationship exists between the potencies in animals and humans and that its parameters can be estimated adequately. Such "scaling rules" have been used to predict the risks of carcinogenicity or other effects. A survey of the literature yielded only a modest number of papers devoted to the validity of these interspecies risk extrapolations, of which approximately 25 attempt quantitative comparisons for either radiation or chemical hazards. Some authors have investigated relatively large data sets in an attempt to identify the scaling rule that provides the best correlation of risks in two or more species. Others have selected a scaling rule and investigated whether its predictions from data in laboratory species match the risks found in humans. Opinion is divided on the validity of specific extrapolation rules and the utility of animal experiments for quantitative risk assessment. Correlations exist among risk levels in various species, but many factors appear to influence toxicity that are not captured in a simple scaling rule such as dose per unit weight or per unit surface area. Although scaling rules are useful, better projections will be made if case-specific factors such as pharmacokinetics can be considered. Further careful comparisons of quantitative risk estimates are needed.

Significant risk decisions in federal regulatory agencies.

The completion of a risk assessment does not reveal whether the assessed risk is of significant public health importance. Little attention has been paid to the development of rigorous analytic approaches to the determination of risk significance. This paper reviews a number of major FDA, EPA, and OSHA decisions regarding significant carcinogenic risks and identifies several problems that need to be explored more fully to ensure that both the qualitative and quantitative features of a risk assessment are considered in the determination of risk significance.