The use and evaluation of primary data in 29 trichloroethylene carcinogen risk assessments

This paper reports the results from a detailed study on how risk assessments of chemicals are actually made. The study is performed by comparing 29 cancer risk assessments made of one and the same chemical substance, namely, trichloroethylene. In this paper, the conclusions that are drawn in these risk assessment documents are described, and differences between the conclusions are explored. This is made within the framework of a proposed cancer risk assessment index. The selection of scientific data for risk assessment purposes is analyzed and the different risk assessors' interpretations and evaluations of individual primary data are compared. It is concluded that the data sets utilized by the trichloroethylene risk assessors are surprisingly incomplete and that biased data selection may have influenced some of the risk assessors' conclusions. Different risk assessors often interpret and evaluate one and the same study in different ways. There are also indications of both interpretation bias and evaluation bias for some of the risk assessors.     

Interpretations of primary carcinogenicity data in 29 trichloroethylene risk assessments.

This paper explores to what extent interpretations of individual primary carcinogenicity data differ between different risk assessors, and discusses possible reasons for such differences as well as their impact on the overall risk assessment conclusions. For this purpose 29 different TCE carcinogenicity risk assessments are used as examples. It is concluded that the TCE risk assessors surprisingly often interpret and evaluate primary data differently. Two particular reasons for differences in data interpretation are discussed: different assessments of statistics, and different assessments of whether the results obtained in bioassays have toxicological relevance. Differences in the interpretation and evaluation of epidemiological data are also explored and discussed.     

Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: an example with trichloroethylene

The guidelines for carcinogen risk assessment recently proposed by the U.S. Environmental Protection Agency (U.S. EPA) provide an increased opportunity for the consideration of pharmacokinetic and mechanistic data in the risk assessment process. However, the greater flexibility of the new guidelines can also make their actual implementation for a particular chemical highly problematic. To illuminate the process of performing a cancer risk assessment under the new guidelines, the rationale for a state-of-the-science risk assessment for trichloroethylene (TCE) is presented. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and most tumors represent an increase in the incidence of a commonly observed, species-specific lesion. A physiologically based pharmacokinetic (PBPK) model was applied to estimate target tissue doses for the three principal animal tumors associated with TCE exposure: liver, lung, and kidney. The lowest points of departure (lower bound estimates of the exposure associated with 10% tumor incidence) for lifetime human exposure to TCE were obtained for mouse liver tumors, assuming a mode of action primarily involving the mitogenicity of the metabolite trichloroacetic acid (TCA). The associated linear unit risk estimates for mouse liver tumors are 1.5 x 10(-6) for lifetime exposure to 1 microg TCE per cubic meter in air and 0.4 x 10(-6) for lifetime exposure to 1 microg TCE per liter in drinking water. However, these risk estimates ignore the evidence that the human is likely to be much less responsive than the mouse to the carcinogenic effects of TCA in the liver and that the carcinogenic effects of TCE are unlikely to occur at low environmental exposures. Based on consideration of the most plausible carcinogenic modes of action of TCE, a margin-of-exposure (MOE) approach would appear to be more appropriate. Applying an MOE of 1000, environmental exposures below 66 microg TCE per cubic meter in air and 265 microg TCE per liter in drinking water are considered unlikely to present a carcinogenic hazard to human health.     

The use of developmental neurotoxicity data in pesticide risk assessments

Following the passage of the Food Quality Protection Act, which mandated an increased focus on evaluating the potential toxicity of pesticides to children, the number of guideline developmental neurotoxicity (DNT) studies (OPPTS 870.6300) submitted to the U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP) was greatly increased. To evaluate the impact of available DNT studies on individual chemical risk assessments, the ways in which data from these studies are being used in pesticide risk assessment were investigated. In addition, the neurobehavioral and neuropathological parameters affected at the lowest observed adverse effect level (LOAEL) for each study were evaluated to ascertain whether some types of endpoints were consistently more sensitive than others. As of December 2008, final OPP reviews of DNT studies for 72 pesticide chemicals were available; elimination of studies with major deficiencies resulted in a total of 69 that were included in this analysis. Of those studies, 15 had been used to determine the point of departure for one or more risk assessment scenarios, and an additional 13 were determined to have the potential for use as a point of departure for future risk assessments (selection is dependent upon review of the entire database available at the time of reassessment). Analysis of parameters affected at the study LOAELs indicated that no single parameter was consistently more sensitive than another. Early assessment time points (e.g., postnatal day (PND) 11/21) tended to be more sensitive than later time points (e.g., PND 60). These results demonstrate that data generated using the current guideline DNT study protocol are useful in providing points of departure for risk assessments. The results of these studies also affirm the importance of evaluating a spectrum of behavioral and neuropathological endpoints, in both young and adult animals, to improve the detection of the potential for a chemical to cause developmental neurotoxicity.     

Indicators of uncertainty in chemical risk assessments

For most of the chemical substances that are subject to regulatory and industrial decision making, important toxicological data are missing. The available dataset is often difficult to interpret, and the differences between alternative, scientifically reasonable interpretations may have major impact on decision making. Since such uncertainties are an important factor in decision making it is essential that they be reported in a transparent and understandable way. In order to clarify how toxicologists report uncertainties, 30 risk assessments for one and the same substance (trichloroethylene) from the years 1973-2001 were searched for phrases indicating uncertainty. These phrases can be divided between four categories: contentual, epistemic, conditionalising, and inferential uncertainty indicators. A typology of uncertainty indicators, based on these categories, is proposed. It is concluded that the use of uncertainty indicators in these texts is not transparent and that the development of standardised uncertainty indicators should significantly improve communications both within the scientific community and between scientists and policymakers.     

Science and transscience in carcinogen risk assessment--the European Union regulatory process for trichloroethylene

This is a study of carcinogen risk assessment of the chlorinated solvent trichloroethylene within the European Union existing substances program and the classification and labeling process. The focus is on the most active and influential participants of this process, namely, those from the United Kingdom, Germany, and Sweden, and from industry. The member state and other experts have different opinions regarding the appropriate classification of trichloroethylene for mutagenicity (no classification or category 3) and carcinogenicity (category 3, 2, or 1). In this article these differences are described, as well as how the primary carcinogenicity and mutagenicity data have been interpreted and evaluated by these participants. It is concluded that underlying the different assessments are disagreements about issues that to some degree lie outside the scope of purely scientific considerations.     

The potential for the use of cell proliferation studies in carcinogen risk assessment

The use of observations on cellular proliferation in assessing the mechanism of action of certain factors in the genesis of tumors of the urinary bladder, forestomach, and intestine, or on the effects of dietary restriction, is illustrated. It is suggested that, particularly with nongenotoxic carcinogens, such studies may be of great use in risk assessment especially for those cases in which animals are exposed at very much higher levels of the test agent in the carcinogenesis bioassay than are humans as the result of the environmental or other use of the agent.     

Comments on article "Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: an example with trichloroethylene" by Clewell and Andersen

In their 2004 article, Clewell and Andersen provide their perspective on the application of mode-of-action (MOA) and pharmacokinetic considerations in contemporary cancer risk assessment using trichloroethylene (TCE) as a case example. TCE is a complex chemical toxicologically, with multiple metabolites, multiple sites of observed toxicity, and multiple potential MOAs. As scientists who are responsible for revising the U.S. Environmental Protection Agency's draft risk assessment of TCE, we welcome input of the quality to which the Agency is held accountable. However, in our view, Clewell and Andersen do not present a sufficiently current, complete, accurate, and transparent review of the pertinent scientific literature. In particular, their article would need to incorporate substantial recently published scientific information, better support its conclusions about MOA and choice of linear or nonlinear dose-response extrapolation, and increase its transparency as to quantitative analyses in order to make a significant contribution to the scientific discussion of TCE health risks.     

Impact of messages about scientific uncertainty on risk perceptions and intentions to use electronic vaping products

BackgroundThe science surrounding e-cigarettes and other electronic vaping products (EVPs) is rapidly evolving, and the health effects of vaping are unclear. Little research has explored how individuals respond to information acknowledging scientific uncertainty. The aim of the present study was to understand the impact of messages about scientific uncertainty regarding the health effects of vaping on risk perceptions and behavioral intentions.MethodsAdults in an online experiment (n = 2508) were randomly exposed to view either a control message (a short factual statement about EVPs) or an uncertainty message (the control message plus additional information describing why EVP-related research is limited or inconclusive). Participants rated the risks of vaping and their intentions to try or stop vaping.ResultsIndividuals who viewed the uncertainty message rated vaping as less risky than those who viewed the control message. Message exposure did not impact intentions to try vaping soon or intentions to stop vaping in the next 6 months.ConclusionsAcknowledging scientific uncertainty made EVP use seem less risky. Future research should explore possible drivers of this response, such as deeper message processing or emotional reactions. Researchers and practitioners designing public health campaigns about vaping might consider a cautious approach to presenting information about scientific uncertainty.     

Applications of mechanistic data in risk assessment: the past, present, and future.

Mechanistic data, when available, have long been considered in risk assessment, such as in the development of the nitrate RfD based on effects in a sensitive group (infants). Recent advances in biology and risk assessment methods have led to a tremendous increase in the use of mechanistic data in risk assessment. Toxicokinetic data can improve extrapolation from animals to humans and characterization of human variability. This is done by the development of improved tissue dosimetry, by the use of uncertainty factors based on chemical-specific data, and in the development of physiologically based pharmacokinetic (PBPK) models. The development of the boron RfD illustrates the use of chemical-specific data in the improved choice of uncertainty factors. The draft cancer guidelines of the U.S. Environmental Protection Agency emphasize the use of mode of action data. The first choice under the guidelines is to use a chemical-specific, biologically based dose-response (BBDR) model. In the absence of a BBDR model, mode of action data are used to determine whether low-dose extrapolation is done using a linear or nonlinear (margin of exposure) approach. Considerations involved in evaluating a hypothesized mode of action are illustrated using 1,3-dichloropropene, and use of a BBDR model is illustrated using formaldehyde. Recent developments in molecular biology, including transgenic animals, microarrays, and the characterization of genetic polymorphisms, have significant potential for improving risk assessments, although further methods development is needed. Overall, use of mechanistic data has significant potential for reducing the uncertainty in assessments, while at the same time highlighting the areas of uncertainty.     

Mechanistic and toxicokinetic data reducing uncertainty in risk assessment

Risk characterization comprises hazard identification describing the intrinsic toxic potential of a chemical, knowledge of dose-response-relationships, as well as of toxicokinetics describing quantitatively the relation between external and internal dose and exposure assessment. Compounds that induce reversible effects, which are repaired during and after exposure, are considered thresholded and allow definition of a NOEL. Biological reactive intermediates of chemicals have the potential to bind covalently to cellular macromolecules like proteins and DNA. Such interaction may not be repaired completely. If damage is not repaired, the effect persists and accumulates upon repeated exposure. In such cases a NOEL cannot be determined. Thus, in the risk assessment process, data on covalent binding (CB) are of qualitative and together with toxicokinetics of quantitative significance. Qualitatively, CB, especially with DNA and in correlation with this to proteins, is indicative for an irreversible and non-thresholded mutagenic and carcinogenic effect. Absence or presence of CB assists to differentiate between primarily genotoxic and thresholded non-genotoxic carcinogens. Quantitatively, toxicokinetics together with CB are used to quantify internal exposure and target dose, which is a prerequisite for species-species extrapolation, and for extrapolation from high dose to low dose. For example, the toxicokinetics of the reactive intermediates of styrene and ethylene have been determined in rodents and humans and modeled to predict dose-responses of internal exposure. It is described in this communication that such information, together with other parameters like cell proliferation as a result of cytotoxicity, is the basis for quantitative risk assessment of human exposure to these compounds. Also for chlorobenzene, the relevance of toxicokinetics for estimating the human health risk is demonstrated.     

The use of epidemiological data in risk assessment

Next to toxicological data, epidemiological studies form the scientific basis for risk assessment. Both approaches have their particular advantages and limitations. The most important limitation of epidemiological studies is the lack of exact data on past exposures. Their most important advantage is that they study the actual occurrence of diseases in humans. Epidemiological and experimental data should be regarded as complementary and should be used in close conjunction in the process of risk assessment. Apart from these advantages and limitations several specific issues are addressed in this paper, such as study populations of particular interest, the problem of low-dose extrapolation, the interpretation of negative results, derivation of no-effect levels from epidemiologic studies, and the application of safety factors for epidemiological studies.     

The human relevant potency threshold: reducing uncertainty by human calibration of cumulative risk assessments

The 2008 National Research Council report "Phthalates and Cumulative Risk Assessment: Tasks Ahead," rejected the underlying premises of TEQ-like approaches - e.g., chemicals are true congeners; are metabolized and detoxified similarly; produce the same biological effects by the same mode of action; exhibit parallel dose response curves - instead asserting that cumulative risk assessment should apply dose addition (DA) to all chemicals that produce "common adverse outcomes" (CAOS). Published mixtures data and a human health risk assessment for phthalates and anti-androgens were evaluated to determine how firmly the DA-CAOS concept is supported and with what level of statistical certainty the results may be extrapolated to lower doses in humans. Underlying assumptions of the DA-CAOS concept were tested for accuracy and consistency against data for two human pharmaceuticals and its logical predictions were compared to human clinical and epidemiological experience. Those analyses revealed that DA-CAOS is scientifically untenable. Therefore, an alternative approach was developed - the Human-Relevant Potency-Threshold (HRPT) - that appears to fit the data better and avoids the contradictions inherent in the DA-CAOS concept. The proposed approach recommends application of independent action for phthalates and other chemicals with potential anti-androgenic properties at current human exposure levels.     

Use of immunotoxicity data in health risk assessments: uncertainties and research to improve the process.

A number of environmental contaminants can suppress immune responses and enhance susceptibility to infectious and/or neoplastic disease. Most of the evidence for immunotoxicity of such contaminants has been obtained from laboratory animal studies and risk assessors must make decisions about risk to the human population based on these studies. Uncertainties associated with this process include determining what level of immune suppression is adverse, extrapolating across species from rodent to human, and across levels of biologic organization from effects on immune function at the cellular level to effects on incidence of disease at the population level, accounting for intra-species variability, and assessing the relationship between effects following acute, subchronic, and chronic exposure. This paper reviews immunotoxicity data that may be applied to the development of risk assessment methods and models designed to reduce some of these uncertainties.     

The use of in vitro data in risk assessment

Describing the toxicological profile of a substance is the first step required for risk assessment. Although a wide range of in vitro methods are widely used to characterise toxicological properties including toxicokinetics, regulatory acceptance is mainly confined to in vitro tests which investigate genotoxic end-points. In vitro tests have been proposed for the endpoints acute toxicity, repeated dose toxicity and toxicity to reproduction which encompass the minimum requirements in the OECD SIDS programme. However, until now, limitations of the proposed tests preclude their application in a regulatory framework. Presently, in vitro tests play a major role in obtaining information on mechanism of toxicity with the perspective to be able to identify pathways of toxic responses by applying toxicogenomics techniques. Physiologically based toxicokinetic modelling is using data from in vitro studies to build up the model for a specific compound. Information from both areas is incorporated into the risk assessment to derive compound-specific safety factors, which account for species differences and for the variability among the human population, including possible sensitive subpopulations. Future developments to further enhance the use of in vitro methods in regulatory toxicology include the development of (Q)SAR approaches supplemented by mechanisms of toxicity, which can be addressed by developing methods of molecular toxicology.     

The use of epidemiology, scientific data, and regulatory authority to determine risk factors in cancers of some organs of the digestive system. 5. Stomach cancer

In 1930, stomach cancer was the leading cause of death due to cancer among men in the United States. Among women it was the third leading cause of cancer deaths. Although it is well known that death rates for stomach cancer have diminished dramatically over the past 50 years, stomach cancer still has the third poorest 5-year relative survival rate of the different cancers, after pancreatic and lung cancer. Most evidence indicates that environmental factors play an important role in the development of stomach cancer. The remarkable decrease in stomach cancer mortality over the past 50 years and the results of a variety of migrant studies support this review. Several published case-control studies have shown positive associations with preserved meat and salted and pickled food in general. However, there are negative associations with vegetables, fruits and milk; vitamin C is implicated. Milk has both positive and negative associations. This points to the possibility of a carcinogen produced by traditional preservation methods such as salting and suggests that fresh vegetables and fruits and high intakes of vitamin C may reduce the risk. What specific role/s the diet plays in the incidence of stomach cancer remains to be seen. There is a need to elaborate the relationship of such factors as age, sex, migration, geography, environmental factors, and diet to the carcinogenic process that produces cancer of the stomach.     

The use of epidemiology, scientific data, and regulatory authority to determine risk factors in cancer of some organs of the digestive system. 2. Esophageal cancer

The epidemiologic aspects of esophageal cancer are well known. The extreme geographical variations in incidence of the disease, the variability in the sex ratio, and the secular trends have been described frequently. The etiology of cancer of the esophagus is known to be complex and composed of multiple factors, those caused by the environment being of greatest importance. The disease preferentially attacks groups with a low socioeconomic status or those hindered by poverty. The esophageal cancer belt has been frequently studied to provide clues to the etiology of esophageal cancer but no definite culprit has yet been found. The majority of the factors so far implicated in cancer of the esophagus appear to act directly on the esophagus rather than systemically. This is an unusual situation in that it enables the disease to be prevented by primary means. There appears to be an enormous disparity in the etiology of the disease among various countries. This disparity may be more apparent than real if the epidemiologic data are interpreted to mean that there is a two-stage process involved, with multiple etiologies for each stage. If we assume that nutritional deficiencies, even subtle ones, predispose the esophagus to influence by carcinogenic substances, the geographic differences fade. Nutritional deficiencies can develop by chronic alcohol use as well as by poverty and lack of an adequate food supply, but diet does not explain the whole picture. External carcinogens are necessary to effect the end result. The culprit may be tobacco in one culture and fungal elements in another. The South African studies which showed an association with tobacco and not alcohol could be explained if we assume that the population's nutritional deficiencies already predisposed the esophagus for the effect of an external carcinogen, thereby making alcohol usage superfluous. It would be helpful if the relationship between esophagitis and nutritional status were elucidated and if it were determined that the condition could be improved or eliminated by dietary factors. The association between nutrition and esophagitis may suggest methods of primary prevention of esophageal cancer and provide a chance of lowering the incidence of this deadly disease.