REGULATORY TOXICOLOGY

Regulatory toxicology is the branch of toxicology (the study of adverse effects of chemicals) that uses scientific knowledge to develop regulations and other strategies for reducing and controlling exposure to dangerous chemicals.

The legal framework in this area is promulgated by governmental agencies. Examples of such agencies in the United States are the Food and Drug Administration (FDA), the Environmental Protection Agency (EPA), and the Occupational Safety and Health Administration (OSHA). Corresponding agencies exist in the European Union (EU) at the national or union level. The primary examples of authorizing legislation in the United States are the Food, Drug, and Cosmetic Act (1938), the Occupational Safety and Health Act (1970), the Clean Air Act (1970), the Federal Insecticide, Fungicide, and Rodenticide Act (1972), the Toxic Substances Control Act (1976), and the Clean Water Act (1977). Corresponding laws exist in the EU.

The Society of Toxicology (United States), EUROTOX (Europe), and the International Union of Toxicology (IUTOX) (global) are major professional organizations. The Society of Toxicology has published a code of ethics for toxicologists that requires its members to:

• Strive to conduct their work and themselves with objectivity and integrity.
• Hold as inviolate that credible science is fundamental to all toxicologic research.
• Seek to communicate information concerning health, safety, and toxicity in a timely and responsible manner, with due regard for the significance and credibility of the available data.
• Present their scientific statements or endorsements with full disclosure of whether or not factual supportive data are available.
• Abstain from professional judgments influenced by conflict of interest and, insofar as possible, avoid situations that imply a conflict of interest.
• Observe the spirit, as well as, the letter of law, regulations, and ethical standards with regard to the welfare of humans and animals involved in their experimental procedures.
• Practice high standards of occupational health and safety for the benefit of their co-workers and other personnel. (Society of Toxicology)

Toxicological Data and Assessment

Toxicity or adverse effects data are obtained either from experimental systems using animals or cell cultures, or from epidemiological studies of humans. The legally required testing differs among groups of chemical substances, ranging from no testing for many industrial chemicals to extensive requirements for pharmaceuticals.

A general problem is that the adverse effects of many chemicals, whether alone or in combination, are unknown. This is due to low data requirements, to statistical limitations in the available data, and to the cocktail effect or the interaction of chemicals. As a rough rule of thumb, epidemiological and experimental studies cannot reliably detect excess incidences of adverse effects of about 10 percent or smaller, and in many cases excess incidences of higher than 10 percent may go undetected. For relatively common types of disease, incidences are between 1 percent (leukemia) and 10 percent (breast cancer in Swedish women). Therefore even in the more sensitive studies, the limits of an observable excess lifetime risk are in the order of 1/100 or 1/1000, a level the public often considers unacceptable.

Once data are collected they are used to formulate toxicological assessments. Toxicological health assessments aim at identifying the potential adverse effects that a substance may cause in humans. This includes a description of the nature of these effects, their likelihood of occurrence, and their extent or severity.

The process of toxicological assessment is usually divided into four steps (National Research Council 1983, European Commission 2003). The first step of hazard identification aims at determining the inherent properties of a substance in order to identify the types of adverse effects to be included in further analysis.

The second step is dose-response assessment. The purpose of the dose-response assessment is to describe the relationship between the size of the dose and the response in the exposed. This is essential, because a high dose of a substance with low toxicity can be lethal, while a very low dose of a substance with high toxicity may be harmless. See Figure 1.

The choice of a toxicological management strategy may depend on whether the dose-response relationship is considered to be linear from zero exposure or if a threshold dose is anticipated. A threshold dose is a dose under which no adverse effects are expected.

The lowest dose that has been shown to give rise to a statistically significant adverse effect compared to unexposed controls is the Lowest Observed Adverse Effect Level (LOAEL). The highest dose that has been administered without any observed statistically significant adverse effect is the No Observed Adverse Effect Level (NOAEL). A benchmark dose (BMD) is obtained by fitting a dose-response model to data, and from that model estimating a dose that corresponds to a predetermined change in the toxicological response investigated. The low-level change in response compared to background associated with the BMD is commonly termed the benchmark response level (BMR). Continuous dose-response data or incidence data may be used as a basis for these calculations. In the latter case, the BMD is generally defined as a 1 percent to 10 percent change in the incidence of the effect compared to background. In any case, the lower 95 percent confidence bound of the benchmark dose (the BMDL) is suggested as an alternative to NOAEL or LOAEL as a starting point for the determination of reference values for estimating acceptable exposure levels. See Figure 2.

The NOAEL, LOAEL, or BMDL should be defined for critical effect. Critical effect is the adverse effect that occurs at the lowest dose.

The third step is exposure assessment. This aims at determining the likelihood of exposure and estimates the magnitude and duration of the doses, as well as the potential exposure routes. Exposure assessment must be based on monitoring data and/or the use of theoretical exposure models.

The final step is risk characterization, which involves comparing the exposure data to the dose-response information in order to characterize the risk in qualitative and (if possible) quantitative terms.

Conclusive dose-response data are rarely available in humans, and therefore risk characterization often involves extrapolation from animal data to assess human risk. Absent contrary evidence, it is generally presumed that the effects seen in the test species under experimental conditions are relevant to humans. This presumption is supported by the fact that common test species are physiologically similar to humans.

In environmental risk assessment the same basic procedure applies. The outcome of hazard identification and dose-response assessment is the Predicted No Effect Concentration (PNEC), and exposure assessment estimates the Predicted Environmental Concentration (PEC). In the risk characterization process, the PEC/PNEC ratios are calculated. Extrapolation is made from experimental data (a limited number of single species) to the ecosystem (millions of species and multiple exposures interacting).

Extrapolation of data is hampered by scientific uncertainty. Resolving all uncertainties inherent in extrapolation would require testing on humans and/or an unreasonable number of animals. The presumptions used to overcome gaps of knowledge in assessment involve value judgments.

Toxicological Management

There are a number of possible risk management options in regulatory toxicology, ranging from public education to the banning of toxic substances. Two central systems are classification with labeling and exposure limits.

The classification and labeling system is an important part of international chemicals control because the classification process constitutes a background for further regulatory actions. According to the criteria for classification, substances (and preparations) are classified according to their inherent properties. Those fulfilling the criteria have to be provided with a warning label. Agenda 21, adopted at the United Nations Conference on Environment and Development in 1992, provided the international mandate to develop a globally harmonized system (GHS) for the classification and labeling of chemicals. The work was coordinated and managed under the auspices of the Inter-organization Programme for the Sound Management of Chemicals (IOMC), administered by the World Health Organization (WHO). The aim is to have the GHS system fully implemented and operational by 2008.

Another major regulatory strategy is the setting of exposure limits. In the workplace such limits are called Occupational Exposure Limits (OEL), or Threshold Limit Values (TLV). Limits for exposure via food and drinking water are called Acceptable (or Tolerable) Daily Intake (ADI or TDI).

A health-based exposure limit is usually derived starting with either an experimentally estimated NOAEL/LOAEL, or a BMDL for the effect of concern. To overcome variability and other uncertainties, the experimental dose level is adjusted with an appropriate uncertainty factor to reach an exposure level assessed as not associated with adverse effects in humans.. The size of the uncertainty factor may vary from one to several thousands depending on the severity of the effect, the nature of the exposure, the exposed population, data-gaps, and uncertainties in the database.

Toxicological management is based on scientific evidence, but in the decision-making process nonscientific considerations are also taken into account. Examples of such considerations are the technical feasibility of the decision including availability of alternative technical processes, socioeconomic consequences, and value-based judgements of what health effects are acceptable.

CHRISTINA RUDÉN

SEE ALSO Radiation;Regulation; Risk;Safety Engineering:Practices;Safety Factors.

BIBLIOGRAPHY

Gad, Shayne C., ed. (2001). Regulatory Toxicology, 2nd edition. London: Taylor and Francis. A reference book of the requirements and regulations that both government agencies and non-government organizations promulgate for establishing the safety of a wide spectra of chemical products. It includes information on the United States, the European, and the Japanese systems, and is aimed for the full range of professionals in this field

National Research Council. (1983). Risk Assessment in the Federal Government—Managing the Process. Washington DC: National Academy Press. This volume evaluates past efforts to develop and use risk assessment guidelines, reviews the experience of regulatory agencies with different administrative arrangements for risk assessment, and evaluates various proposals to modify procedures. The book's conclusions and recommendations can be applied across the entire field of environmental health.

National Research Council, Committee on Risk Assessment of Hazardous Air Pollutants, Board on Environmental Studies and Toxicology, Commission on Life Sciences. (1994). Science and Judgement in Risk Assessment. Washington DC: National Academy Press. This report is aimed at a multidisciplinary audience with different levels of technical understanding. It addresses for instance the background of risk assessment and current practice at EPA, specific concerns in risk assessment, such as extrapolations, and cross-cutting issues that affect all parts of risk assessment. For example, how should uncertainty be handled?

Rudén, Christina. (2003). "Science and Transscience in Carcinogen Risk Assessment—The European Regulatory Process for Trichloroethylene." Journal of Toxicology and Environmental Health, part B: Critical Reviews 6(3): 257–277. In this article the European Union regulatory process for classification and labelling is described, it also reports an example of how hazard assessments are performed within this legislation.

Van Leeuwen, Cornelis Johannes: Josephus Ludovicus: and Maria Hermens, eds. (1995). Risk Assessment of Chemicals: An Introduction. Dordrecht, The Netherlands: Kluwer Academic Publishers. This book provides an introduction to risk assessment and management of chemicals, including background information on sources and emissions, distribution and fate processes, toxicology and ecotoxicology, and basic principles and methods for hazard and risk assessment within the legislative framework. It is intended for students and professionals within this field.

INTERNET RESOURCES

European Commission (2003). "Technical Guidance Document on Risk Assessment." Available from http://ecb.jrc.it. This is a set of technical guidance is issued by the European Commission as a help to carry out the risk assessments required within the EU legislations. It includes technical details for conducting hazard identification, dose - response assessment, exposure assessment and risk characterisation in relation to human health and the environment.

Society of Toxicology. Code of ethics. Available from http://www.toxicology.org/memberservices/aboutsot/ethics.html.