On the Relationship Between Carcinogenicity and Acute Toxicity

Parodi et al. ⁽¹⁾ and Zeise et al. ⁽²⁾ found a surprising statistical correlation (or association) between acute toxicity and carcinogenic potency. In order to shed light on the questions of whether or not it is a causal correlation, and whether or not it is a statistical or tautological artifact, we have compared the correlations for the NCI/NTP data set with those for chemicals not in this set. Carcinogenic potencies were taken from the Gold et al. database. We find a weak correlation with an average value of TD₅₀/LD₅₀= 0.04 for the non-NCI data set, compared with TD₅₀/LD₅₀= 0.15 for the NCI data set. We conclude that it is not easy to distinguish types of carcinogens on the basis of whether or not they are acutely toxic.     

An Overview of the Report: Correlation Between Carcinogenic Potency and the Maximum Tolerated Dose: Implications for Risk Assessment

Current practice in carcinogen bioassay calls for exposure of experimental animals at doses up to and including the maximum tolerated dose (MTD). Such studies have been used to compute measures of carcinogenic potency such as the TD₅₀ as well as unit risk factors such as q ₁ * for predicting low-dose risks. Recent studies have indicated that these measures of carcinogenic potency are highly correlated with the MTD. Carcinogenic potency has also been shown to be correlated with indicators of mutagenicity and toxicity. Correlation of the MTDs for rats and mice implies a corresponding correlation in TD₅₀ values for these two species. The implications of these results for cancer risk assessment are examined in light of the large variation in potency among chemicals known to induce tumors in rodents.     

Development of a Unit Risk Factor for 1,3-Butadiene Based on an Updated Carcinogenic Toxicity Assessment

The Texas Commission on Environmental Quality (TCEQ) has developed an inhalation unit risk factor (URF) for 1,3-butadiene based on leukemia mortality in an updated epidemiological study on styrene-butadiene rubber production workers conducted by researchers at the University of Alabama at Birmingham. Exposure estimates were updated and an exposure estimate validation study as well as dose-response modeling were conducted by these researchers. This information was not available to the U.S. Environmental Protection Agency when it prepared its health assessment of 1,3-butadiene in 2002. An extensive analysis conducted by TCEQ discusses dose-response modeling, estimating risk for the general population from occupational workers, estimating risk for potentially sensitive subpopulations, effect of occupational exposure estimation error, and use of mortality rates to predict incidence. The URF is 5.0 × 10⁻⁷ per μg/m³ or 1.1 × 10⁻⁶ per ppb and is based on a Cox regression dose-response model using restricted continuous data with age as a covariate, and a linear low-dose extrapolation default approach using the 95% lower confidence limit as the point of departure. Age-dependent adjustment factors were applied to account for possible increased susceptibility for early life exposure. The air concentration at 1 in 100,000 excess leukemia mortality, the no-significant-risk level, is 20 μg/m³ (9.1 ppb), which is slightly lower than the TCEQ chronic reference value of 33 μg/m³ (15 ppb) protective of ovarian atrophy. These values will be used to evaluate ambient air monitoring data so the general public is protected against adverse health effects from chronic exposure to 1,3-butadiene.     

Concordance of Carcinogenic Response between Rodent Species: Potency Dependence and Potential Underestimation

The use of average qualitative concordance between two bioassay endpoints is considered, with emphasis directed at agreement between rats and mice from results of long-term carcinogenicity studies. It is noted that concordance varies as a function of the underlying potency or toxicity of the chemicals over which the averaging is performed. Thus, the averaging process dilutes large observed concordances from potent chemicals, and possibly inflates lower observed concordances from weakly active chemicals. Stratification over some measure of potency is suggested as a method for taking these effects into account. Statistical simulations of concordance analyses limited to low-potency ranges are employed to examine the concordance measure in greater detail. It is seen that at low potencies, observed concordance is consistently underestimated, reaching maximum levels of only about 80%.     

Use of Mechanistic Models to Estimate Low-Dose Cancer Risks

The utility of mechanistic models of cancer for predicting cancer risks at low doses is examined. Based upon a general approximation to the dose-response that is valid at low doses, it is shown that at low doses the dose-response predicted by a mechanistic model is a linear combination of the dose-responses for each of the physiological parameters in the model that are affected by exposure. This demonstrates that, unless the mechanistic model provides a theoretical basis for determining the dose-responses for these parameters, the extrapolation of risks to low doses using a mechanistic model is basically "curve fitting," just as is the case when extrapolating using statistical models. This suggests that experiments to generate data for use in mechanistic models should emphasize measuring the dose-response for dose-related parameters as accurately as possible and at the lowest feasible doses.     

Reducing Risk on Machinery: A Field Evaluation Pilot Study of Risk Assessment

A pilot evaluation of the ANSI B11-TR3 Machinery Risk Assessment/Risk Reduction (RA/RR) Guideline was conducted. The TR3 guideline was introduced into five companies on one machinery system in each company with a second machine system serving as a control. A pre-post investigation was performed with safety conditions measured pre and post in both treatment and control and with risk reduction score measured only in the treatment machine system. NIOSH provided a commercially available risk assessment software to facilitate the process. Evaluation measures included avoided injuries, reduced exposure to machinery hazards, pretest and posttest knowledge demonstration, assessment of group processes following training, correct implementation of the guidelines, and degree to which risk reduction recommendations were implemented. The qualitative results of this pilot effort appear to be the best indicators for the way ahead in industrial machine risk assessment. All companies indicated that they derived value in participating in this study and in conducting risk assessments. Quantitative study results suggest that: (1) as measured by the knowledge of the participants before and after the TR3 training, the guidelines can be effective at enhancing employee knowledge of safe machine operations and (2) although the injury reduction trends appear successful, the small sample size in the study size should be considered in interpreting these early results.     

How Reassuring are Risk Comparisons to Pollution Standards and Emission Limits?

Pollutant emissions or ambient levels are often justified by reference to a higher benchmark, such as a public health standard or permit limit. However, does this risk comparison persuade the public audiences to whom it is frequently directed that such pollution levels are “acceptable”? A substantial proportion of people living within one mile of New Jersey's industrial facilities, perhaps as much as half, is indeed reassured by a comparison to such benchmarks. Positive attitudes toward discharge limits were linked to speaking English at home; positive attitudes toward drinking water standards were associated with seeing local benefits of industry as outweighing its risks, not speaking English, and relative youth (49 years old or less). Three scenarios involving drinking water contamination varied pre‐ and post‐treatment levels of the pollutant, though all post‐treatment levels were below the standard. In all cases great concern was expressed, with no significant differences across scenarios; net benefits, being white, and non‐English speaking were linked to lower concern. Relative trust seems a better explanation of different attitudes toward benchmark comparisons than varying levels of knowledge, but both hypotheses have drawbacks that merit further testing. These results imply that people with negative views of industry or government, the ones officials might most wish to reassure, will tend to doubt that regulatory benchmarks offer a valid risk comparison.     

Evaluation of Developmental Toxicity Data: A Discussion of Some Pertinent Factors and a Proposal

There is currently no well-accepted standard method for evaluation of developmental toxicity data. This paper presents one approach to the evaluation of developmental toxicity data. We initially identify some pertinent factors that influence the interpretation of animal data and summarize the literature pertaining to these factors. Such factors include the quality and quantity of data and the relationship between maternal and developmental toxicity. We proceed with a discussion of quantitative assessment of data and propose schemes for qualitative and quantitative developmental hazard assessments.     

Interspecific Scaling of Toxicity Data

This paper reexamines the scaling approaches used in cancer risk assessment and proposes a more precise body weight scaling factor. Two approaches are conventionally used in scaling exposure and dose from experimental animals to man: body weight scaling (used by FDA) and surface area scaling (BW0.67--used by EPA). This paper reanalyzes the Freireich et al. (1966) study of the maximum tolerated dose (MTD) of 14 anticancer agents in mice, rats, dogs, monkeys, and humans, the dataset most commonly cited as justification for surface area extrapolation. This examination was augmented with an analysis of a similar dataset by Schein et al. (1970) of the MTD of 13 additional chemotherapy agents. The reanalysis shows that BW0.75 is a more appropriate scaling factor for the 27 direct-acting compounds in this dataset.     

The Multistage Model with a Time-Dependent Dose Pattern: Applications to Carcinogenic Risk Assessment1

A cancer risk assessment methodology based upon the Armitage–Doll multistage model of cancer is applied to animal bioassay data. The method utilizes the exact time-dependent dose pattern used in a bioassay rather than some single measure of dose such as average dose rate or cumulative dose. The methodology can be used to predict risks from arbitrary exposure patterns including, for example, intermittent exposure and short-term exposure occurring at an arbitrary age. The methodology is illustrated by applying it to a National Cancer Institute bioassay of ethylene dibromide in which dose rates were modified several times during the course of the experiment.     

Correlation Between Carcinogenic Potency of Chemicals in Animals and Humans

Twenty-three chemicals were selected for comparison of the carcinogenic potencies estimated from epidemiological data to those estimated from animal carcinogenesis bioassays. The chemicals were all those for which reasonably strong evidence of carcinogenicity could be found in humans or animals and for which suitable data could be obtained for quantifying carcinogenic potencies in both humans and animals. Many alternative methods of analyzing the bioassay data were investigated. Almost all of the methods yielded potency estimates that were highly correlated with potencies estimated from epidemiological data; correlations were highly statistically significant (p less than 0.001), with the corresponding correlation coefficients ranging as high as 0.9. These findings provide support for the general use of animal data to evaluate carcinogenic potential in humans and also for the use of animal data to quantify human risk.     

Risk Assessment for Aflatoxin: An Evaluation Based on the Multistage Model

Lifetime cancer potency of alfatoxin was assessed based on the Yeh et al. study from China in which both aflatoxin exposure and hepatitis B prevalence were measured. This study provides the best available information for estimating the carcinogenic risk posed by aflatoxin to the U.S. population. Cancer potency of aflatoxin was estimated using a biologically motivated risk assessment model. The best estimate of aflatoxin potency was 9 (mg/kg/day)⁻¹ for individuals negative for hepatitis B and 230 (mg/kg/day)⁻¹ for individuals positive for hepatitis B.     

Estimation of Acute Toxicity by Fitting a Dose-Time-Response Surface

In acute toxicity testing, organisms are continuously exposed to progressively increasing concentrations of a chemical and deaths of test organisms are recorded at several selected times. The results of the test are traditionally summarized by a dose-response curve, and the time course of effect is usually ignored for lack of a suitable model. A model which integrates the combined effects of dose and exposure duration on response is derived from the biological mechanisms of aquatic toxicity, and a statistically efficient approach for estimating acute toxicity by fitting the proposed model is developed in this paper. The proposed procedure has been computerized as software and a typical data set is used to illustrate the theory and procedure. The new statistical technique is also tested by a data base of a variety of chemical and fish species.     

The Social Benefits of Expedited Risk Assessments

The present regulation of carcinogens is quite slow; hundreds of substances that have tested positive for carcinogenicity in animal bioassays have not been addressed by the U.S. regulatory system. This carries with it unappreciated social, economic, and public health costs. However, there are readily available expedited approximation procedures for assessing the potency of carcinogens whose use has substantial benefits that outweigh any costs from less science-intensive and less extensively documented assessments. These benefits can be seen by using a model to suggest the magnitude of social costs in regulating carcinogens by current conventional methods compared with expedited procedures for assessing the potency of known carcinogens. Two scenarios, one in accordance with current agency presumptions and one which assumes extreme unreliability in animal data and in the accuracy of potency assessments, compare conventional science-intensive and expedited procedures. On both, the total social costs of expedited procedures are lower than conventional procedures across a wide range of values assigned for individual mistakes of under regulation and over regulation. It appears better to evaluate a larger universe of known carcinogens somewhat less intensively for each substance than to evaluate a small proportion of that same universe very carefully and delay considering the rest.     

How Tautological Are Interspecies Correlations of Carcinogenic Potencies?

Crouch and Wilson demonstrated a strong correlation between carcinogenic potencies in rats and mice, supporting the extrapolation from mouse to man. Bernstein et al. , however, show that the observed correlation is mainly a statistical artifact of bioassay design. Crouch et al. have a comeback. This paper will review the arguments and present some new data. The correlation is largely (but not totally) tautological, confirming results in Bernstein et al.     

Public Views on Drinking Water Standards as Risk Indicators

Government agencies often compare contaminant levels to standards and other regulatory benchmarks to convey relative risk to public audiences, as well as for enforcement. Yet we know little of how citizens interpret these risk indicators or factors influencing interpretations. Owners of private residential wells in New Jersey were surveyed by mail. A majority appreciated this comparison, trusted the standard, and could effectively compare the contaminant level to the standard. Most people who recalled that their own well water quality was unsatisfactory simply installed treatment systems. However, there was also a surprising amount of inability to tell whether pollution levels were better or worse than the standard, perhaps exacerbated by confusing institutional language to summarize the comparison (e.g., pollution “exceeds” or is “less than” the standard) and innumeracy. There was also substantial skepticism about the degree to which pollution levels below, or (to a lesser extent) above, the standard are harmless or harmful, respectively. Skepticism was variously due to distrust of standards, disbelief in thresholds for health effects, inability to accurately compare standards and contaminant levels, information processing, and demographics. Discontinuity in reactions below versus above the standard did not exist in the aggregate, and rarely among individuals, contrary to some previous findings. At identical standards and contaminant levels, familiar toxins (mercury, arsenic, lead) elicited higher risk ratings than less familiar ones. Given the wide institutional use of this risk indicator, further research on how to improve the design and use of this indicator, and consideration of alternatives, is warranted.     

A Method for Comparing the Impact on Carcinogenicity of Tobacco Products: A Case Study on Heated Tobacco Versus Cigarettes

Comparing the harmful health effects related to two different tobacco products by applying common risk assessment methods to each individual compound is problematic. We developed a method that circumvents some of these problems by focusing on the change in cumulative exposure (CCE) of the compounds emitted by the two products considered. The method consists of six steps. The first three steps encompass dose-response analysis of cancer data, resulting in relative potency factors with confidence intervals. The fourth step evaluates emission data, resulting in confidence intervals for the expected emission of each compound. The fifth step calculates the change in CCE, probabilistically, resulting in an uncertainty range for the CCE. The sixth step estimates the associated health impact by combining the CCE with relevant dose-response information. As an illustrative case study, we applied the method to eight carcinogens occurring both in the emissions of heated tobacco products (HTPs), a novel class of tobacco products, and tobacco smoke. The CCE was estimated to be 10- to 25-fold lower when using HTPs instead of cigarettes. Such a change indicates a substantially smaller reduction in expected life span, based on available dose-response information in smokers. However, this is a preliminary conclusion, as only eight carcinogens were considered so far. Furthermore, an unfavorable health impact related to HTPs remains as compared to complete abstinence. Our method results in useful information that may help policy makers in better understanding the potential health impact of new tobacco and related products. A similar approach can be used to compare the carcinogenicity of other mixtures.     

Combined Effects of Contaminant Desorption and Toxicity on Risk from PAH Contaminated Sediments

A strong inverse correlation was observed between the polycyclic aromatic hydrocarbon (PAH) mass fraction desorbed, a surrogate measure of bioavailability, and relative carcinogenicity, as quantified by potency equivalency factors (PEFs), for two study sediments from the New York/New Jersey Harbor estuary. Because compounds with the highest toxicity, such as dibenz(a,h)anthracene and benzo(a)pyrene (BAP), also tended to be the least rapidly and least extensively desorbed, the U.S. Environmental Protection Agency (EPA) default guidance may dramatically overestimate risk from exposure to PAH-contaminated soils or sediments. A "relative risk index" (RRI) was developed to account for the combined effects of compound-specific bioavailability and toxic potency in estimating excess cancer risk. Using this approach, estimated excess cancer risk may be diminished by as much as a factor of 159 times versus default EPA guidance. Also, the hierarchy of estimated risk between study sediments and among treatment fractions of study sediments differed using the two approaches, implying that the default approach may inaccurately determine site clean-up priorities. The percentage contribution of each potentially carcinogenic priority PAH to total excess cancer risk was computed under various scenarios. In each case, the contribution of BAP to total excess cancer risk was remarkably invariable, for example, ranging from 48% to 52% in one sediment, and 44% to 54% in the other, over four different exposure durations. These results suggest that BAP may be an excellent indexing compound for gauging relative exposure risk across sediments. Other important contributors to total excess cancer risk were benz(a)anthracene and dibenz(a,h)anthracene. Together, these three compounds comprised nearly 90% of total excess cancer risk from all PAHs in every scenario. This integrated RRI approach may enable regulators to more accurately gauge relative risks and make more informed sediment management decisions.     

Industrial Machine Systems Risk Assessment: A Critical Review of Concepts and Methods

Reducing the risk of work-related death and injury to machine operators and maintenance personnel poses a continuing occupational safety challenge. The risk of injury from machinery in U.S. workplaces is high. Between 1992 and 2001, there were, on average, 520 fatalities per year involving machines and, on average, 3.8 cases per 10,000 workers of nonfatal caught-in-running-machine injuries involving lost workdays. A U.S. task group recently developed a technical reference guideline, ANSI B11 TR3, "A Guide to Estimate, Evaluate, & Reduce Risks Associated with Machine Tools," that is intended to bring machine tool risk assessment practice in the United States up to or above the level now required by the international standard, ISO 14121. The ANSI guideline emphasizes identifying tasks and hazards not previously considered, particularly those associated with maintenance; and it further emphasizes teamwork among line workers, engineers, and safety professionals. The value of this critical review of concepts and methods resides in (1) its linking current risk theory to machine system risk assessment and (2) its exploration of how various risk estimation tools translate into risk-informed decisions on industrial machine system design and use. The review was undertaken to set the stage for a field evaluation study on machine risk assessment among users of the ANSI B11 TR3 method.