The ToxCast program for prioritizing toxicity testing of environmental chemicals.

The U.S. Environmental Protection Agency (EPA) is developing methods for utilizing computational chemistry, high-throughput screening (HTS), and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources toward chemicals that likely represent the greatest hazard to human health and the environment. This chemical prioritization research program, entitled "ToxCast," is being initiated with the purpose of developing the ability to forecast toxicity based on bioactivity profiling. The proof-of-concept phase of ToxCast will focus upon chemicals with an existing, rich toxicological database in order to provide an interpretive context for the ToxCast data. This set of several hundred reference chemicals will represent numerous structural classes and phenotypic outcomes, including tumorigens, developmental and reproductive toxicants, neurotoxicants, and immunotoxicants. The ToxCast program will evaluate chemical properties and bioactivity profiles across a broad spectrum of data domains: physical-chemical, predicted biological activities based on existing structure-activity models, biochemical properties based on HTS assays, cell-based phenotypic assays, and genomic and metabolomic analyses of cells. These data will be generated through a series of external contracts, along with collaborations across EPA, with the National Toxicology Program, and with the National Institutes of Health Chemical Genomics Center. The resulting multidimensional data set provides an informatics challenge requiring appropriate computational methods for integrating various chemical, biological, and toxicological data into profiles and models predicting toxicity.     

U.S. EPA's IRIS assessment of 2-butoxyethanol: the relationship of noncancer to cancer effects

U.S. EPA's integrated risk information system (IRIS) assessment of 2-butoxyethanol (EGBE) indicates that the human carcinogenic potential of EGBE cannot be determined at this time, but that “suggestive evidence” for cancer exists from laboratory animal studies (hemangiosarcoma of the liver in male mice and forestomach squamous cell papilloma or carcinoma in female mice [National Toxicology Program (NTP), 2000a. Toxicology and carcinogenesis studies of 2-butoxyethanol (CAS no. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series No. 484. U.S. Department of Health and Human Services, National Institutes of Health, Washington, DC]). Since the last EGBE IRIS assessment, a number of studies have provided evidence that the carcinogenic effects observed in mice are nonlinear in their mode of action and may be dependent on threshold events such as EGBE-induced hemolytic effects. EPA is in the process of considering several questions relating to this issue. First, can a plausible mode of action be determined for the two types of tumors observed in mice? Second, are the mechanisms involved applicable to humans? If so, should the mode of action be considered to result in a linear or nonlinear dose–response? These questions will be addressed within the context of the agency's new cancer guidelines and with regard to how the answers might affect a revised IRIS assessment for EGBE.     

Proceedings of the Hydrogen Sulfide Health Research and Risk Assessment Symposium October 31-November 2, 2000

The Hydrogen Sulfide Health Research and Risk Assessment Symposium came about for several reasons: (1) increased interest by the U.S. Environmental Protection Agency (EPA) and several state agencies in regulating hydrogen sulfide (H₂S); (2) uncertainty about ambient exposure to H₂S; (3) confusion and disagreement in the literature about possible health effects at low-level exposures; and (4) presentation of results of a series of recent animal bioassays. The American Petroleum Institute (API) proposed this symposium and the EPA became an early co-sponsor, with the Chemical Industry Institute of Toxicology (CIIT) and the American Forest & Paper Association (AF&PA) contributing expertise and funding assistance. The topics covered in this symposium included Animal Research, Human Research, Mode-of-Action and Dosimetry Issues, Environmental Exposure and Monitoring, Assessment and Regulatory Issues, and closed with a panel discussion. The overall goals of the symposium were to: gather together experts in H₂S health effects research and individuals from governmental agencies charged with protecting the public health, provide a venue for reporting of recent research findings, identify gaps in the current information, and outline new research directions and promote research collaboration. During the course of the symposium, presenters provided comprehensive reviews of the state of knowledge for each topic. Several new research proposals discussed at the symposium have subsequently been initiated. This report provides a summary of the talks, poster presentations, and panel discussions that occurred at the Hydrogen Sulfide Health and Risk Assessment Symposium.     

Zebrafish developmental screening of the ToxCast™ Phase I chemical library

Zebrafish (Danio rerio) is an emerging toxicity screening model for both human health and ecology. As part of the Computational Toxicology Research Program of the U.S. EPA, the toxicity of the 309 ToxCast? Phase I chemicals was assessed using a zebrafish screen for developmental toxicity. All exposures were by immersion from 6–8 h post fertilization (hpf) to 5 days post fertilization (dpf); nominal concentration range of 1 nM–80 μM. On 6 dpf larvae were assessed for death and overt structural defects. Results revealed that the majority (62%) of chemicals were toxic to the developing zebrafish; both toxicity incidence and potency was correlated with chemical class and hydrophobicity (logP); and inter-and intra-plate replicates showed good agreement. The zebrafish embryo screen, by providing an integrated model of the developing vertebrate, compliments the ToxCast assay portfolio and has the potential to provide information relative to overt and organismal toxicity.     

Derivation of biomonitoring equivalent (BE) values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds: a screening tool for interpretation of biomonitoring data in a risk assessment context

Recent efforts by the U.S. Centers for Disease Control and Prevention and other researchers have resulted in a growing database of measured concentrations of dioxins and related compounds in blood samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring equivalent (BE) values are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments This study reviews available health based exposure guidance values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds from a variety of agencies including the World Health Organization Joint Expert Committee on Food Additives (JECFA), the European Commission Scientific Committee on Foods (ECSCF), the United Kingdom Committee on Toxicology (UKCOT), and the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) to estimate corresponding BE values for dioxin-like compounds in blood on a serum lipid-adjusted basis. Based on data from the animal studies underlying the exposure guidance values, a serum lipid-adjusted dioxin toxicity equivalent (TEQ) concentration of approximately 15 ppt is consistent with the ATSDR minimal risk level (MRL) for dioxins. Serum lipid-adjusted TEQ concentrations of approximately 31 to 74 ppt are consistent with the tolerable intakes estimated by the other three agencies. These values may be used as screening tools for evaluation of biomonitoring data for dioxins in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for dioxins.     

Derivation of Biomonitoring Equivalents for di(2-ethylhexyl)phthalate (CAS No. 117-81-7)

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of an environmental chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for di(2-ethylhexyl)phthalate (DEHP) from Health Canada, the United States Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), the European Chemicals Bureau (ECB), and the European Food Safety Authority (EFSA). BE values corresponding to the oral reference dose (RfD), minimal risk level (MRL) or tolerable daily intake (TDI) estimates from these agencies were derived based on data on excretion fractions of key urinary metabolites. BE values based on the sum of three, four, and five of the most predominant and commonly-measured metabolites of DEHP are presented. These values may be used as screening tools for evaluation of biomonitoring data for DEHP metabolites in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for DEHP relative to other chemicals.     

Proceedings of the Hydrogen Sulfide Health Research and Risk Assessment Symposium October 31-November 2, 2000

The Hydrogen Sulfide Health Research and Risk Assessment Symposium came about for several reasons: (1) increased interest by the U.S. Environmental Protection Agency (EPA) and several state agencies in regulating hydrogen sulfide (H2S); (2) uncertainty about ambient exposure to H2S; (3) confusion and disagreement in the literature about possible health effects at low-level exposures; and (4) presentation of results of a series of recent animal bioassays. The American Petroleum Institute (API) proposed this symposium and the EPA became an early co-sponsor, with the Chemical Industry Institute of Toxicology (CIIT) and the American Forest & Paper Association (AF&PA) contributing expertise and funding assistance. The topics covered in this symposium included Animal Research, Human Research, Mode-of-Action and Dosimetry Issues, Environmental Exposure and Monitoring, Assessment and Regulatory Issues, and closed with a panel discussion. The overall goals of the symposium were to: gather together experts in H2S health effects research and individuals from governmental agencies charged with protecting the public health, provide a venue for reporting of recent research findings, identify gaps in the current information, and outline new research directions and promote research collaboration. During the course of the symposium, presenters provided comprehensive reviews of the state of knowledge for each topic. Several new research proposals discussed at the symposium have subsequently been initiated. This report provides a summary of the talks, poster presentations, and panel discussions that occurred at the Hydrogen Sulfide Health and Risk Assessment Symposium.     

Medium- and high-throughput screening of neurotoxicants using C. elegans

The U.S. National Toxicology Program, the U.S. Environmental Protection Agency, and other national and international agencies are committing significant resources towards the development of alternative species to be used as replacements for mammalian models in toxicological studies. Caenorhabditis elegans is a well-characterized soil nematode that is becoming a useful model in the assessment of neurotoxicants. To determine the effects of potential neurotoxicants on C. elegans, four medium-throughput (feeding, growth, reproduction and locomotion) and two high-throughput (growth and reproduction) assays have been developed. Three of these assays use the COPAS Biosort, a flow cytometer capable of rapidly measuring thousands of nematodes in minutes. Medium-throughput feeding, growth, and reproduction assays were used to assess the toxicity of eight suspected neurotoxicants. For several of the neurotoxicants examined, significant effects were observed at similar concentrations between assays. High-throughput reproduction and growth assays were used to estimate the toxicity of thousands of chemicals in two libraries. These assays will prove useful in evaluating the role of alternative toxicological models in tiered toxicity testing of thousands of chemicals.     

Derivation of Biomonitoring Equivalents for di-n-butyl phthalate (DBP), benzylbutyl phthalate (BzBP), and diethyl phthalate (DEP)

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for di-n-butyl phthalate (DBP), benzylbutyl phthalate (BzBP), and diethyl phthalate (DEP) from Health Canada, the United States Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), and the European Food Safety Authority (EFSA). BE values corresponding to the oral reference dose (RfD), minimal risk level (MRL) or tolerable daily intake (TDI) estimates from these agencies were derived for each compound based on data on excretion fractions of key urinary metabolites. These values may be used as screening tools for evaluation of biomonitoring data for metabolites of these three phthalate compounds in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for each of these compounds relative to other chemicals.     

EPA's Neurotoxicity Risk Assessment Guidelines

The proposed Neurotoxicity Risk Assessment Guidelines (U.S.EPA, 1995c Fed Reg. 60(192), 52032–52056) of the U.S.Environmental Protection Agency (EPA) were the subject of aworkshop at the 1997 Meeting of the Society of Toxicology. Theworkshop considered the role of guidelines in the risk assessmentprocess, the primary features, scientific basis, and implicationsof the guidelines for EPA program offices, as well as for industrialneurotoxicologists from the perspectives of both pesticidesand toxic substances regulation. The U.S. National Academy ofSciences (NAS, 1983, Risk Assessment in the Federal Government:Managing the Process) established a framework for distinguishingrisk management from risk assessment, the latter being the resultof integrating hazard identification, hazard characterization,and exposure assessment data. The guidelines are intended toestablish operating principles that will be used when examiningdata in a risk assessment context. The proposed neurotoxicityrisk assessment guidelines provide a conceptual framework fordeciding whether or not a chemically induced effect can be consideredto be evidence of neurotoxicity. Topics in the proposed guidelinesinclude structural and functional effects, dose-response andduration considerations, and relationships between effects.Among the issues that must be considered are the multiplicityof chemical effects, the levels of biological organization inthe nervous system, and the tests, measurements, and protocolsused. Judgment of the adversity of an effect depends heavilyon the amount and types of data available. The attribution ofa chemically induced effect to an action on the nervous systemdepends on several factors such as the quality of the study,the nature of the outcome, dose-response and time-response relationships,and the possible involvement of nonneural factors. The guidelineswill also serve as a reference for those conducting neurotoxicitytesting, as well as establish a consistent approach to neurotoxicityrisk assessment by regulators. Extending this approach throughinternational harmonization would be advantageous to the developmentof products for a worldwide market. Thus, both risk assessorsand regulated industries have a large stake in the guidelinesto provide a framework that will lead to accurate risk assessmentdecisions.     

The proportions of mutagens among chemicals in commerce

It has been estimated that there are approximately 80,000 chemicals in commerce. Thus, it is not possible to test all these substances for mutagenicity and carcinogenicity; it is possible, however, to test or make estimates from selected subsets of these chemicals. For example, in the U.S. National Toxicology Program (NTP), 35% of the chemicals tested for mutagenicity in Salmonella were positive, as were 52% of the chemicals tested for carcinogenicity in rodents. In contrast, in the U.S. EPA Gene-Tox database, the proportions of chemicals that are Salmonella mutagens is 56%. These and other databases may be biased toward positive responses because they generally have been developed to look at specific structural or use classes of chemicals or chemicals suspected of genetic or carcinogenic activity. To address the question of the proportions of mutagens among all chemicals in commerce, a database of 100 chemicals was created from a random selection of chemicals in commerce. These chemicals were tested for mutagenicity in Salmonella and 22% were mutagenic. The mutagenicity of the 46 highest U.S. production organic chemicals was also compiled; 20% were mutagenic. These values provide a more accurate estimate of the proportions of mutagens among chemicals in commerce than can be derived from published mutagenicity databases.     

Toxicology at the Food and Drug Administration: new century, new challenges

Dr. Schwetz is the Acting Deputy Commissioner of the Food and Drug Administration (FDA). He was Director of FDA National Center for Toxicological Research in Jefferson, AR, from 1993 to 1999. A diplomate of the American Board of Toxicology, Dr. Schwetz was acting Director of the Environmental Toxicology Program at the National Institutes of Health National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, NC, before coming to the FDA in 1993. He was also Associate Director of the National Toxicology program there. He had been Chief of the Institute Systems Toxicity Branch since 1982. Dr. Schwetz currently serves as Adjunct Professor, Department of Pharmacology and Toxicology/Division of Interdisciplinary Toxicology, at the University of Arkansas for Medical Sciences. He was editor of Fundamental and Applied Toxicology from 1986 to 1992, and serves on the Editorial Advisory Board of Environmental Health Perspectives and Critical Reviews in Toxicology. Dr. Schwetz is an invited member of the Canada Health Protection Branch Science Advisory Board, and an elected member of the National Academy of Sciences Institute of Medicine. He is a member of the Society of Toxicology (SOT) and the National Capitol Area Chapter, SOT; the American Veterinary Medical Association; National Society of Phi Zeta, Honor Society of Veterinary Medicine; Teratology Society; Behavioral Teratology Society; and the Reproductive Toxicology Specialty Section of the SOT. He is past president of the Reproductive Toxicology Specialty Section of the SOT and of the North Carolina and the South Central Chapters of the SOT. In addition to numerous other professional awards during his career, Dr. Schwetz received the U.S. Government 1998 Meritorious Executive Presidential Rank Award.     

Improving the U.S. EPA toxic release inventory database for environmental health research

In 1986, Congress passed the Emergency Planning and Community Right‐to‐Know Act (EPCRA) in response to the tragic death of thousands of people in Bhopal, India, following the accidental release of the toxic gas methyl isocyanate (MIC) from a Union Carbide facility. As a component of EPCRA, certain manufacturers are required to report annually the total mass (pounds per year, 1b/yr) of toxic chemicals released into the environment (air, water, land, or underground injection), treated on‐site, or shipped off‐site for further waste treatment. This information is compiled by the U.S. Environmental Protection Agency (EPA) into a publicly accessible database known as the Toxic Release Inventory (TRI). The TRI database is designed to encourage pollution prevention and waste reduction by increasing public access to and knowledge of environmental chemical releases. EPCRA has been generally considered by industry, government, and community representatives as one of the most successful environmental laws in U.S. history. Over the past few years, EPA has initiated a three‐phased expansion to EPCRA reporting requirements that will enhance the overall usefulness of the TRI database. The focus of this article is to discuss these changes and highlight several current uses of the TRI database in environmental health research.     

Derivation of Biomonitoring Equivalents for di(2-ethylhexyl)phthalate (CAS No. 117-81-7)

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of an environmental chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for di(2-ethylhexyl)phthalate (DEHP) from Health Canada, the United States Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), the European Chemicals Bureau (ECB), and the European Food Safety Authority (EFSA). BE values corresponding to the oral reference dose (RfD), minimal risk level (MRL) or tolerable daily intake (TDI) estimates from these agencies were derived based on data on excretion fractions of key urinary metabolites. BE values based on the sum of three, four, and five of the most predominant and commonly-measured metabolites of DEHP are presented. These values may be used as screening tools for evaluation of biomonitoring data for DEHP metabolites in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for DEHP relative to other chemicals.     

Chemical scoring system for hazard and exposure identification

To assist in the preliminary evaluation of compounds of toxicological and environmental interest to the U.S. Environmental Protection Agency (EPA), a scoring system was devised as a collaborative effort between the EPA and the Oak Ridge National Laboratory. The scoring system combines objective guidelines with professional judgment to evaluate chemicals and consists of 11 separate scoring parameters, 6 of which pertain directly to toxicity, e.g., aquatic toxicity and oncogenicity. The remaining parameters are related to environmental fate and occupational, consumer, and environmental exposure. The scoring system was designed to rapidly score chemicals in a minimal amount of time with readily available information. It is used by the Office of Toxic Substances of the EPA as a tool to help set priorities in conjunction with other criteria. It is particularly useful in performing preliminary evaluations involving large chemical classes, such as petroleum distillates.     

A critical evaluation of the use of mutagenesis, carcinogenesis, and tumor promotion data in a cancer risk assessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Regulatory agencies in the Western Hemisphere are currently assessing the potential human health risks of environmental contamination by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Some U.S. agencies such as the Environmental Protection Agency (EPA) and Centers for Disease Control (CDC) have assumed that TCDD behaves as a tumor initiator in animals and have used linear low-dose mathematical extrapolation models for estimating any human risk. In contrast, the Ontario Ministry of the Environment, the State Institute of National Health of The Netherlands, and the Federal Environmental Agency of the Federal Republic of Germany have concluded that TCDD does not have initiator activity; these agencies have advocated a risk extrapolation approach which applies a safety factor to a no-observable-effect level. Estimations of the potential risk obtained by these two approaches can differ by three to four orders of magnitude and have a major impact on the allocation of resources within the affected countries. This paper critically reviews the TCDD bacterial, animal, and human data on mutagenesis, carcinogenesis, and tumor promotion and concludes that the scientific evidence does not support risk estimations which are based on TCDD as a tumor initiator. Rather, the animal data overwhelmingly support TCDD as a tumor promoter. Risk estimations which incorporate tumor promotion activity more accurately reflect the scientific understanding of TCDD's mechanism of action and provide better estimates of its risk.     

Data gaps in toxicity testing of chemicals allowed in food in the United States

In the United States, chemical additives cannot be used in food without an affirmative determination that their use is safe by FDA or additive manufacturer. Feeding toxicology studies designed to estimate the amount of a chemical additive that can be eaten safely provide the most relevant information. We analyze how many chemical additives allowed in human food have feeding toxicology studies in three toxicological information sources including the U.S. Food and Drug Administration's (FDA) database. Less than 38% of FDA-regulated additives have a published feeding study. For chemicals directly added to food, 21.6% have feeding studies necessary to estimate a safe level of exposure and 6.7% have reproductive or developmental toxicity data in FDA's database. A program is needed to fill these significant knowledge gaps by using in vitro and in silico methods complemented with targeted in vivo studies to ensure public health is protected.     

Workshop overview: reassessment of the cancer risk of dichloromethane in humans.

The U.S. Environmental Protection Agency (U.S. EPA) classifies dichloromethane (DCM) as a "probable human carcinogen," based upon its risk assessment conducted in the late 1980s (http://www.epa.gov/iris/subst/0070.htm). Since that time, cancer risk-assessment practices have evolved, leading to improved scientifically based methods for estimating risk and for illuminating as well as reducing residual uncertainties. A new physiologically based pharmacokinetic (PBPK) model has been developed, using data from human volunteers exposed to low DCM levels, that provides new information on the human to human variability in DCM metabolism and elimination (L. M. Sweeney et al., 2004, Toxicol. Lett. 154, 201-216). This information, along with data from other published human studies, has been used to develop a new cancer risk estimation model utilizing probabilistic methodology similar to that employed recently by U.S. EPA for other chemicals (ENVIRON Health Sciences Institute, 2005, Development of population cancer risk estimates for environmental exposure to dichloromethane using a physiologically based pharmacokinetic model. Final Report to Eastman Kodak Company). This article summarizes the deliberations of a scientific peer-review panel convened on 3 and 4 May 2005 at the CIIT Centers for Health Research in Research Triangle Park, North Carolina, to review the "state of the science" for DCM and to critically evaluate the new information for its utility in assessing potential human cancer risks from DCM exposure. The panel (Melvin E Andersen, CIIT Centers for Health Research, Research Triangle Park, NC 27709; A. John Bailer, Miami University, Scripps Gerontology Center, Oxford, OH 45056; Kenneth S. Crump, ENVIRON Health Sciences Institute, Ruston, LA 71270; Clifford R. Elcombe, University of Dundee, Biomedical Research Centre, Dundee DD1 9SY, United Kingdom; Linda S. Erdreich, Exponent, 420 Lexington Avenue, Suite 1740, New York, NY 10170; Jeffery W. Fisher, University of Georgia, Department of Environmental Health Science, Athens, GA 30602; David Gaylor, Gaylor and Associates, LLC, Eureka Springs, AR 72631; F Peter Guengerich, Vanderbilt University, Department of Biochemistry, Nashville, TN 37232; Kenneth Mundt, ENVIRON Health Sciences Institute, Amherst, MA 01004; Lorenz R Rhomberg, Gradient Corporation, Cambridge, MA 021138; Charles Timchalk, Pacific Northwest National Laboratory, Richland, WA 99352), chaired by M.E.A., was composed of experts in xenobiotic metabolism and carcinogenic mechanisms, PBPK modeling, epidemiology, biostatistics, and quantitative risk assessment. Observers included representatives from U.S. EPA, CIIT, and Eastman Kodak Company (Kodak), as well as several consultants to Kodak. The workshop was organized and sponsored by Kodak, which employs DCM as a solvent in the production of imaging materials. Overall, the panel concluded that the new models for DCM risk assessment were scientifically and technically sound and represented an advance over those employed in past assessments.     

Neurotoxic substances also posing a cancer risk: A warning

A large proportion of compounds studied for their neurotoxic potential are at the same time suspected or proven carcinogens. This is demonstrated using the International Neurotoxicology Association (INA) Professional Interest Directory and publications from the field of neurotoxicology as examples. In addition to listing these compounds, the classification scheme used by the International Agency for Research on Cancer (IARC), the Commission of the European Communities (EC), the U.S. Environmental Protection Agency (EPA), the German MAK-Commission of the Deutsche Forschungsgemeinschaft (DGF) and the U.S. National Institute of Occupational Safety and Health (NIOSH) to make qualitative risk assessments is explained. Finally, a short initiation to quantitative risk assessment as performed by the US EPA and the World Health Organization (WHO) is given in order to put the reader into a position as to assess the cancer risk incurred by his/her co-workers and by himself.