Recent criticisms of the conduct and use of risk assessment by regulatory agencies have led to a wide range of proposed remedies, including changes in regulatory statutes and the development of new methods for assessing risk. The mandate to this Committee was more limited. Our objective was to examine whether alterations in institutional arrangements or procedures, particularly the organizational separation of risk assessment from regulatory decision-making and the use of uniform guidelines for inferring risk from available scientific information, can improve federal risk assessment activities. Before undertaking to determine whether organizational and procedural reforms could improve the performance and use of risk assessment in the federal government, the Committee examined the state of risk assessment and the regulatory environment in which it is performed. In this chapter, we define risk assessment and differentiate it from other elements in the regulatory process, analyze the types of judgments made in risk assessment, and examine its current government context. Because one chronic health hazard, cancer, was highlighted in the Committee's congressional mandate and has dominated public concern about public health risks in recent years, most of our report focuses on it. Furthermore, because activities in four agencies--the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), the Occupational Safety and Health Administration (OSHA), and the Consumer Product Safety Commission (CPSC)--have given rise to many of the proposals for changes in risk assessment practices, our review focuses on these four agencies. The conclusions of this report, although directed primarily at risk assessment of potential carcinogens as performed by these four agencies, may be applicable to other federal programs to reduce health risks.

There are three different approaches to chemical risk assessment which will be considered in this paper. The U.S. Environmental Protection Agency(EPA) Cancer Risk Assessment includes some of the approaches used by the International Agency for Research on Cancer (IARC). The Agency for Toxic Substances and Disease Registry (ATSDR) effort is an evaluated database approach similar to that used in the National Institute for Occupational Safety and Health (NIOSH) Criteria Documents and in the documentations prepared by the Occupational Safety and Health Administration (OSHA) for the Permissible Exposure Limits (PELs) and those of the American Conference of Governmental Industrial Hygienists (ACGIH) for the Threshold Limit Values (TLVs). A third approach is used by the Committee on Toxicology.

Hazardous wastes released into the general environment are of concern to the public and to public health authorities. In response to this concern, the Comprehensive Environmental Response, Compensation, and Liability Act, as amended (commonly called Superfund), was enacted in 1980 to provide a framework for environmental, public health, and legal actions concerning uncontrolled releases of hazardous substances. The Agency for Toxic Substances and Disease Registry (ATSDR) was created by Superfund to address the public health issues of hazardous wastes in the community environment. Two key Agency programs, Public Health Assessments and Toxicological Profiles, are designed to assess the risk to human health of exposures to hazardous substances that migrate from waste sites or through emergency releases (e.g., chemical spills). The Agency's public health assessment is a structured process that permits ATSDR to identify which waste sites or other point sources require traditional public health actions (e.g.. human exposure studies, health studies, registries, health surveillance, health advisories). The ATSDR qualitative public health assessment complements the U.S. Environmental Protection Agency's quantitative risk assessment. For Superfund purposes, both assessments are sitespecific. ATSDR's toxicological profiles are prepared for priority hazardous substances found most frequently at Superfund sites. Each profile presents the current toxicologic and human health effects information about the substance being profiled. Each profile also contains Minimal Risk Levels (MRLs), a type of risk assessment value. This paper covers ATSDR's experience in conducting public health assessments and developing MRLs, and it relates this experience to recommendations on how to improve chemical risk assessments.

The fundamental assumption that thresholds exist for noncarcinogenic toxic effects of chemicals is reviewed; this assumption forms the basis for the no-observed-effect level/ safety-factor (NOEL/SF) approach to risk assessment for such effects. The origin and evolution of the NOEL/SF approach are traced, and its limitations are discussed. The recently proposed use of dose-response modeling to estimate a benchmark dose as a replacement for the NOEL is explained. The possibility of expanding dose-response modeling of non carcinogenic effects to include the estimation of assumed thresholds is discussed. A new method for conversion of quantitative toxic responses to a probability scale for risk assessment via dose-response modeling is outlined.

Although animal studies have been used most often for quantitative risk assessment, it is generally recognized that well-conducted epidemiologic studies would provide the best basis for estimating human risk. However, there are several features related to the design and analysis of epidemiologic studies that frequently limit their usefulness for quantitating risks. The lack of accurate information on exposure in epidemiologic studies is perhaps the most frequently cited limitation of these studies for risk assessment. However. other features of epidemiologic study design, such as statistical power, length of follow-up, confounding, and effect modification, may also limit the inferences that can be drawn from these studies. Furthermore, even when the aforementioned limitations are overcome, substantial uncertainty exists concerning the choice of an appropriate statistical (or biologic) model for extrapolation beyond the range of exposures observed in a particular study. This paper focuses on presenting a review and discussion of the methodologic issues involved in using epidemiologic studies for risk assessment. This review concentrates on the use of retrospective, cohort, mortality studies of occupational groups for assessing cancer risk because this is the most common application of epidemiologic data for quantitative risk assessment (QRA). Epidemiologic data should not be viewed as a panacea for the problems inherent in using animal bioassay data for QRA. Rather, information that can be derived from epidemiologic and toxicologic studies complement one another, and both data sources need to be used to provide the best characterization of human risk.

The assessment of exposure is an important component of the risk assessment process. Exposure information is used in risk assessment in at least two ways: 1) in the identification of hazards and the epidemiologic research investigating exposure-response relationships and 2) in the development of population exposure estimates. In both of these cases, the value of a chemical risk assessment is enhanced by improvements in the quality of exposure assessments. The optimum exposure assessment is the direct measurement of population exposure; however, such measurements are rarely available. Recent developments in methods for exposure assessment allow estimates to be made that are valid representations of actual exposure. The use of these exposure estimates to classify exposures correctly enhances the likelihood that causal associations between exposure and response will be correctly identified and that population risks will be accurately assessed.

As currently conducted, standard rodent bioassays do not provide sufficient information to assess carcinogenic risk to humans at doses thousands of times below the maximum tolerated dose. Recent analyses indicate that measures of carcinogenic potency from these tests are restricted to a narrow range about the maximum tolerated dose and that information on shape of the dose-response is limited in experiments with only two doses and a control. Extrapolation from high to low doses should be based on an understanding of the mechanisms of carcinogenesis. We have postulated that administration of the maximum tolerated dose can increase mitogenesis which, in turn. increases rates of mutagenesis and, thus, carcinogenesis. The animal data are consistent with this mechanism, because about half of all chemicals tested are indeed rodent carcinogens, and about 40% of the positives are not detectably mutagenic. Thus, at low doses where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than commonly assumed. In contrast, for high-dose exposures in the workplace, assessment of hazard requires comparatively little extrapolation. Nevertheless. permitted workplace exposures are sometimes close to the tumorigenic dose-rate in animal tests. Regulatory policy to prevent human cancer has primarily addressed synthetic chemicals, yet similar proportions of natural chemicals and synthetic chemicals test positive in rodent studies as expected from an understanding of toxicological defenses, and the vast proportion of human exposures are to natural chemicals. Thus, human exposures to rodent carcinogens are common. The natural chemicals are the control to evaluate regulatory strategies, and the possible hazards from synthetic chemicals should be compared to the possible hazards from natural chemicals. Qualitative extrapolation of the carcinogenic response between species has been investigated by comparing two closely related species: rats and mice. Overall predictive values provide moderate confidence in interspecies extrapolation; however, knowing that a chemical is positive at any site in one species gives only about a 50% chance that it will be positive at the same site in the other species.

Current risk assessment practices largely reflect the need for a consistent set of relatively rapid, first-cut procedures to assess 'plausible upper limits' of various risks. These practices have important roles to play in 1) screening candidate hazards for initial attention and 2) directing attention to cases where moderate-cost measures to control exposures are likely to be warranted, in the absence of further extensive (and expensive) data gathering and analysis. A problem with the current practices, however, is that they have led assessors to do a generally poor job of analyzing and expressing uncertainties, fostering 'One-Number Disease' (in which everything from one's social policy position on risk acceptance to one's technical judgment on the likelihood of different cancer dose-response relationships is rolled into a single quantity). At least for analyses that involve relatively important decisions for society (both relatively large potential health risks and relatively large potential economic costs or other disruptions), we can and should at least go one further step - and that is to assess and convey both a central tendency estimate of exposure and risk as well as our more conventional 'conservative' upper-confidence-limit values. To accomplish this, more sophisticated efforts are needed to appropriately represent the likely effects of various sources of uncertainty along the casual chain from the release of toxicants to the production of adverse effects. When the effects of individual sources of uncertainty are assessed (and any important interactions included), Monte Carlo simulation procedures can be used to produce an overall analysis of uncertainties and to highlight areas where uncertainties might be appreciably reduced by further study. Beyond the information yielded by such analyses for decision-making in a few important cases, the value of doing several exemplary risk assessments in. this way is that a set of benchmarks can be defined that will help calibrate the assumptions used in the larger number of risk assessments that must be done by 'default' procedures.

Scientists have long used conventional toxicological methods to establish 'safe levels of exposure' for chemicals presumed to have threshold health effects or doses below which significant effects are unlikely to occur. These same methods cannot be used to establish safe levels of exposure for non-threshold pollutants. such as carcinogens. Therefore. Federal regulatory agencies in the United States are using risk assessment methods to provide information for public health policy decisions concerning increases in risk associated with increases in exposure to carcinogenic and other non-threshold pollutants. Acceptable exposure/risk levels are decided by policymakers who consider descriptions and estimates of risks together with social and economic benefits from the uses of the chemical. 1bis paper focuses on the development of quantitative risk assessment approaches by Federal regulatory agencies in the United States, and identifies the mathematical models currently being used for risk extrapolation. including their inherent uncertainties. The uncertainties and limitations of these methods have led some scientists to question the utility of quantitative risk extrapolation. The experience of the; U.S. Environmental Protection Agency (EPA). as summarized in this paper. can provide a realistic basis for evaluating the pros and cons. Finally. shortcomings in current risk assessment methods and their use in policy decisions are explored. and areas for possible improvement. given current scientific knowledge. are identified.

This paper presents a brief survey of current methodology available for quantitative risk assessment of environmental carcinogens. Four current models for low-dose extrapolation are reviewed. Current problems and controversies and possible options in doing quantitative risk assessments based on chronic animal studies are discussed.

Eletrophysiological methods revealed subclinical neuropathy in 26 workers, exposed from 1 to 17 years to lead and whose blood lead (PbB) values had never exceeded $70{\mu}g/100\;ml$, as ascertained by checking the monitor reports of the factory and by careful exposure history. The PbB determinations had been tested repostedly and had been found valid. The main findings were slowing of the maximal motor conduction velocities of the median and ulnar nerves and particularly the conduction velocity of the slower fibers of the ulnar nerve. Eletrophysiological abnormalities comprised fibriliations, diminution of the number of motor units on maximal contraction, and an abnormal. Thus, a dose-response relationship exlets on a group basis. Since the regular monitoring of PbBs in most workers during their entire period of exposure excludes the possibility of a body burden out of proportion to the PbBs silght neuro-logical damage is produced at exposures hitherto regarded as quite sale.

A subgroup or workers from a secondary lead smelter was defined to include those with blood lead levels not exceeding $80{\mu}g/100\;ml$ and with no pest history of elevated blood lead. Central nervous system symptoms (tiredness, sleeplessness, irritability, headache) were reported by 55% of the group and muscle and joint pain by 39%. Zinc proteporphyrin (ZPP) levels were elevated in 71% or cases. Low hemoglobin levels (less than 14 gm/l00 ml) were round in more than a third of the workers. While BUN and creatinine were mostly in the normal range, there - nevertheless n correlation between ZPP and both BUN and creatinine. Reduced nerve-conduction velocities were present in 25% or the group; this was not significantly different from findings in Ii control group. The data indicate that n blood level of $80{\mu}g/100\;ml$ is an inappropriate biological guide in the prevention or lead disease.

Williams, M K., King, E., and Walford, Joan (1969). Brit. J. industr. Med., 26, 202-216. An investigation of lead absorption in an electric accumulator factory with the use of personal samplers. Thirty-nine lead workers and controls, in stable conditions of exposure, each wore personal lead-in-air samplers daily for two weeks. During the second week samples for blood lead, urinary lead, urinary coproporphyrin, urinary $\gamma$-aminolevulinic acid (ALA), the punctate basophil count, and haemoglobin were taken daily. Duplicate estimations were made on one day. The lead exposures of men doing almost identical jobs differed by ratios of up to four to one. This could be attributed on y to personal differences in working habits. The correlation coefficients and regression equations of the biochemical tests with lead-in-air and with each other were determined. The mean values and $95\%$ confidence limits of single determinations of some of the biochemical tests corresponding to the two commonly accepted TLVs of lead-in-air (0-20 and 0-15 mg./$m^{3}$) were calculated from the regression equations. For each biochemical test the variation due to analytical error, the variation from day to day within subjects and the residual variation about the regression on lead-in-air were calculated. Previous estimates of the latter are not known. Excessive confidence may be placed in an index of exposure due to its low coefficient of variation within subjects unless the coefficient of variation between subjects about regression is taken into account. The correction for specific gravity of estimations of lead and ALA in spot samples of urine was found to reduce slightly the residual variation between subjects about the regression on lead-in-air and to increase the correlations with lead-in-air and with the other biochemical tests, but these changes were not statistically significant. The modified method used for estimating blood lead and urinary lead is described and validated.

The relation between lead in air (PbA) and lead in blood (PbB), concentrations was investigated among 44 workers in five major operations in a United States high volume, lead acid battery plant. The study covered a 30 month period in which workers received frequent PbA and PbB determinations, workers remained in a single job, and PbA concentrations averaged below the US Occupational Safety and Health Administration (OSHA) permissible exposure limit of $50{\mu}g/m^{3}$. In both univariate and multivariable linear regressions, longitudinal analyses averaging PbA concentrations over the 30 month study period appeared superior to cross sectional analyses using only six month PbA averages .to model PbB concentrations. The covariate adjusted coefficient ($\alpha$ value) for PbA($\mu/m^{3}$) in models of PbB (${\mu}g/100\;g$) was 1-14. This figure is strikingly higher than that reported in previous studies in the lead acid battery industry in all of which PbA concentrations were substantially higher than in the current study. Plausible explanations for the differences in a: values include non-linearity of the PbA-PbB curve, a higher fraction of large size particulate associated with higher PbA concentrations, survivor bias among workers exposed to higher PbA concentrations, and the cross sectional designs of most previous studies. Despite previously reported problems with the model used by OSHA to predict PbA-PbB relations, the findings of this study are in good agreement with the predictions of that model.

The region of the respiratory tract where inhaled particles deposit can have important implications for the causation of local or systemic toxic effects. For most aerosols of occupational importance, respiratory tract deposition can be predicted from the aerodynamic diameter of the particles. With the advent of cascade impactors, particularly those of personal sampler size, the determination of the aerodynamic diameters of aerosols has become more common. Some limitations of cascade impactor use are well recognized (e.g., particle bounce and substrate overloading) and are generally correctable. However, two important limitations of the instruments may not be receiving adequate attention: relative humidity effects on potentially hygroscopic aerosols and the collection characteristics of fibrous aerosols as compared to their actual deposition site potential. The results of this study, when compared to results of previous controlled laboratory trials, suggest that, while potentially hygroscopic lead aerosols from lead acid battery plant operations do not appear to be affected by changes in plant environmental humidity levels, the potential - exists for significant size changes upon inhalation. Secondly, fibers were detected in aerodynamic size ranges that would be associated with deep lung deposition; however, upon microscopic examination, these same fibers would actually be predicted to deposit in the upper airways. This study suggests that the physicalchemical properties and morphological features of an aerosol should be carefully considered by industrial hygienists before cascade impactors are used in attempts to predict the effects of inhaled aerosols.

To assess quantitatively the association between benzene exposure and leukemia, we examined the mortality rate of a cohort with occupational exposure to benzene. Cumulative exposure for each cohort member was estimated from historical air-sampling data and, when no sampling data existed, from interpolation on the basis of existing data. The overall standardized mortality ratio (a measure of relative risk multiplied by 100) for leukemia was 337 (95 percent confidence interval, 154 to 641), and that for multiple myeloma was 409 (95 percent confidence interval, 110 to 1047). With stratification according to levels of cumulative exposure, the standardized mortality ratios for leukemia increased from 109 to 322, 1186, and 6637 with increases in cumulative benzene exposure from less than 40 parts per million-years (ppm-years), to 40 to 199, 200 to 399, and 400 or more. respectively. A cumulative benzene exposure of 400 ppm years is equivalent to a mean annual exposure of 10 ppm over a 40-year working lifetime; 10 ppm is the currently enforceable standard in the United States for occupational exposure to benzene. To examine the shape of the exposure-response relation, we performed a conditional logistic-regression analysis, in which 10 controls were matched to each cohort member with leukemia. From this model, it can be calculated that protection from benzene induced leukemia would increase exponentially with any reduction in the permissible exposure limit.

The American Conference of Governmental Industrial Hygienists (ACGIH) has proposed a threshold limit value (TLV) for benzene of 0.1 ppm. Individuals representing the American Petroleum Institute (API)and the Chemical Manufacturers Association (CMA) have argued that 1) the risk assessment by Rinsky .et al. which ACGIH partially relied upon for its proposed TLV overestimates the risk; however, at the exposures levels of interest - (e.g., 0.1 to 1.0 ppm) for establishing a benzene TLV, the Rinsky et al. assessment provides lower estimates of leukemia risk than most others; 2) ACGIH should not use the Dow study for direct observational evidence of leukemia risk associated with low-level benzene exposure because of confounding exposure; however, it is unlikely that confounding exposures played a role in the excess of leukemia demonstrated in the study, and the Dow cohort was exposed to an average benzene concentration of about 5.5 ppm benzene for 7.11 years (31:1.5 ppm-years), while some of the individuals in the study who died from leukemia were exposed to an average of only 1.0 ppm without the opportunity for highpeak exposures; 3) the Occupational Safety and Health Administration (OSHA) established an 8-hour time-weighted average (TWA) of 1.0 ppm in 1987, and there is no new evidence that would justify reducing the TWA below that level; however, the OSHA TWA of 1.0 ppm was based on economic feasibility and the level of excess risk remaining at 1.0 ppm, i.e., 10 excess leukemia deaths per 1000 workers over an occupational lifetime (45 years) according to OSHA's preferred estimate leaves behind I risk considered significant by OSHA. In addition, chromosomal studies among workers and in animals exposed to benzene indicate that low-level exposure, i.e., 1.0 ppm, is associated with elevated Cytogenetic damage. On the basis of adverse health effects data alone, in this author's opinion, it would be poor science and poor public health policy to establish a benzene TLV greater than 0.1 ppm.