Environmental Risk Assessment Reports - Chapter 29

CHAPTER 29 International Health Risk Assessment Approaches for Pesticides Colleen J. Dragula Johnson and Gary J. Burin CONTENTS I. Introduction.................................................................................................527 II. Sources of Information...............................................................................528 III. Differences in Policy and Objectives.........................................................528 IV. Performing Assessments.............................................................................531 V. Issues Affecting Risk Assessment Decisions.............................................534 VI. Status of International Harmonization Efforts...........................................533 VII. Conclusion..................................................................................................534 References...................................................................................................534 I. INTRODUCTION The procedure for conducting risk assessments was originally developed by the National Academy of Sciences in the early 1980s and contained four steps: hazard identification, dose-response assessment, exposure assessment, and risk character-ization. This same basic method continues to be used today as the basis for assessing chemicals. Despite the general scientific consensus on the individual components of a risk assessment, substantial differences exist in the numerical values calculated. This chapter compares and contrasts the techniques used by various countries for assessing the risks associated with pesticide substances. Particular emphasis is placed on quantitating cancer risk, a contentious area within the scientific and regulatory communities for many years. In addition, the impact of mechanism of action (i.e., genotoxic and nongenotoxic) is emphasized, since this often drives the assessment procedures used by countries. 527 © 2001 by CRC Press LLC 528 A PRACTICAL GUIDE TO ENVIRONMENTAL RISK ASSESSMENT REPORTS In order to provide more consistency between countries on the methods used to assess risk, a number of scientific meetings and conferences have discussed inter-national harmonization efforts. To determine the status of this issue within the international community, the International Programme on Chemical Safety (IPCS) sponsored a project utilizing a survey questionnaire to obtain information on assess-ment techniques utilized by 21 Organisation for Economic Cooperation and Devel-opment (OECD) and select nonOECD countries. Several review articles and docu-ments have also been prepared on this topic, especially in relation to carcinogenicity (GAO, 1993; OTA, 1993; WHO, 1993). Finally, this chapter addresses a number of policy and technical issues relating to risk assessment. To the extent possible, updates on changes in policy have been included. The primary goal is to highlight differences that currently exist between the U.S. and other countries. II. SOURCES OF INFORMATION It is sometimes difficult to identify the appropriate governing body or group within a regulatory agency to contact with questions concerning risk assessment procedures. GAO (1993) provides a schematic breakdown of the regulatory agency structures in select OECD countries. In addition, the Pesticide Regulation Compendium (PRC, 1993) comprehensively describes the pesticide regulations in over 100 countries, including a description of each country’s regulatory system, data requirements for residues, toxicology, ecotoxicology, and labeling. Table 1 lists the addresses for select regulatory agencies involved in conducting risk assessments. III. DIFFERENCES IN POLICY AND OBJECTIVES To investigate the intercountry differences in approaches to risk assessment, two components of the process have been examined: hazard identification and dose-response. Hazard identification examines all available data in humans and laboratory animals relating to a chemical’s potential to induce toxicity. For carcinogenicity, the International Agency for Research on Cancer (IARC) uses an alphanumeric classi-fication scheme to characterize whether the chemical is a known, probable, or possible human carcinogen. Although the U.S. EPA formerly used an alphanumeric system, in April 1996 it published new cancer risk assessment guidelines (U.S. EPA, 1996). These new guidelines proposed the use of three descriptive categories, similar to those used in the European Union (EU)* to characterize cancer risk (Directive 67/548/EEC).** Although assignment of these qualitative cancer ratings tends to be * The European Community (now called the European Union) was established in 1958 by the Treaty of Rome and is responsible for developing governmental policy primarily through legislation known as regulations and directives. Much of the legislation affecting environmental issues involves directives. These directives are binding on the member nations with respect to the end result, but allow each state to individually decide the means by which they will implement the directive (OTA, 1993). This allows for considerable flexibility in fine-tuning the specifics of the directives. ** EU Directive 67/548/EEC addresses the classification, packaging, and labeling of dangerous sub-stances and was last appended by the Seventh Amendment. Annex VI of this directive provides guidance for characterizing the carcinogenicity of chemicals in the EU. © 2001 by CRC Press LLC INTERNATIONAL HEALTH RISK ASSESSMENT APPROACHES FOR PESTICIDES 529 Table 1 Australia Bulgaria Canada China Regulatory Agencies Responsible for Conducting Pesticide Risk Assessments The Scientific Director Chemicals Safety Unit DHHLGCS, PO Box 9848 Canberra ACT 2601 National Center of Hygiene Ecology and Nutrition D. Nestorov Str. 15 1431 Sofia, Bulgaria Director General Food Directorate Health Protection Branch Health and Welfare Canada Health Protection Branch Bldg.,Tunney’s Pasture Ottawa, Ontario Canada K1A OL2 Institute for the Control of Agrochemicals, Ministry of Agriculture (ICAMA) Liang Maqiao, Chaoyang Qu, Beijing 100026, China Czechoslovakia Egypt France Germany India Korea Thailand United States National Institute of Public Health, National Reference Centre for Pesticides Srobarova 48, 100 42 Prana 10 Czech Republic Central Agricultural Pesticides Lab Ministry of Agriculture Dekki, Giza, Egypt DGCCRF Commission of Toxicity 59 Boulevard Vincent Auriol, 75703 Paris cedex 13 Bundesgesundheitsamt 1. Eachgebeit C I 4 2. Postfach 33 00 13 3. B-1000 Berlin 33 4 Secretary, Central Insecticides Board & Registration Committee Directorate of P.P.Q & S NH-IV, Faridabad 121001 Agricultural Chemicals Research Institute 249 SeudoonDong SuweonSi KyunggiDo Republic of Korea Director of Agricultural Regulatory Division Department of Agriculture Bangkok 10900 Office of Pesticide Programs, Health Effects Division Environmental Protection Agency Washington, DC fairly consistent between countries, the situation for the dose-response evaluation is significantly different. In the U.S., dose-response data are frequently assumed to be linear in the non-experimental low-dose region and are assessed through the derivation of cancer potency factors. Using mathematical models (i.e., the linearized multistage model, see below), upper limits of risk are calculated that yield a cancer potency factor. This factor is multiplied by the estimated exposure to yield a single risk value. In actuality, the “true” risk actually lies between this calculated upper limit (i.e., 95th percentile) and zero (EPA,1989). The 15 EU member nations (Austria, Belgium, Denmark, Finland, France, Ger-many, Greece, Ireland, Italy, Luxembourg, The Netherlands, Portugal, Spain, Swe-den, and the U.K.) use a significantly different approach than the U.S. for assessing the dose-response of carcinogenic pesticides. In these countries, cancer is thought to be a threshold response yielding a “safe” dose below which there is no risk. The EU also focuses on mechanism of action (e.g., genotoxic vs. nongenotoxic) in dealing with carcinogenic or potentially carcinogenic pesticides; registration of pesticides which are genotoxic is not permitted. Acceptable daily intakes (ADIs) are derived for nongenotoxic pesticides using NOELs or NOAELs* from animal carci- * The NOAEL is the highest dose administered that produces “no statistically or biologically significant increases in frequency or severity of adverse effects.’’ The NOEL is defined in the same manner, with the exception that there is no increase in the frequency or severity of effects (Hallenbeck and Cunningham, 1985). © 2001 by CRC Press LLC 530 A PRACTICAL GUIDE TO ENVIRONMENTAL RISK ASSESSMENT REPORTS nogenicity studies. This approach has occasionally been applied in the U.S. to assess pesticides for which the weight-of-evidence for carcinogenicity is not convincing. Thus, the use of a threshold-based approach in the U.S. is a function of the weight-of-evidence rather than whether or not genotoxicity is presumed to be responsible for tumor induction. Given the release of the new cancer risk assessment guidelines, however, the procedures used by the U.S. may change. Health Canada reported employing different risk assessment techniques depend-ing on the mechanism of tumor induction. For genotoxic pesticides, a quantitative risk assessment is performed whereas for nongenotoxic pesticides an ADI is derived in conjunction with a weight-of-evidence assessment (Dragula and Burin, 1994). Specific information on the type of quantitative risk assessment model used was not supplied. Typically, the federal government is responsible for these assessments, and not the individual provinces within Canada. Publicly available information on pes-ticide regulatory practices can be obtained through “Backgrounders” published by the Pesticides Directorate. For occupational exposures, Denmark, The Netherlands, and the U.K. use quan-titative risk assessment techniques (i.e., mathematical models) to generate a risk value which represents the probability of human cancer risk. This probability reflects the expected or the best estimate of the human cancer risk likely to occur in a population. Finally, a significant portion of countries simply adopt the carcinogenicity assess-ment policies or evaluations developed by other countries or scientific groups. For example, Bulgaria and Thailand rely on the evaluations derived by MARC (which provides statements regarding the weight-of-evidence for carcinogenicity based on animal and epidemiological data); Korea relies on the risk assessment techniques and decisions developed by the EPA; Egypt utilizes the evaluations provided by the Joint FAO/WHO Meeting on Pesticide Residues; Czechoslovakia uses the risk assessment methods developed by WHO in their Environmental Health Criteria document (WHO, 1990); and Spain relies on criteria described in Annex VI of the EU Directive 67/548/EEC for dangerous substances (Dragula and Burin, 1994). The most outstanding difference between the risk assessment goals or objectives in the U.S. vs. the EU is the default assumption in the U.S. that carcinogenicity is a nonthreshold, or linear process where every increase in dose is associated with an increased risk. The U.S. has utilized the linearized, multistage model for most potential human carcinogens, including pesticides, whereas the EU has generally used the ADI approach. The U.S. also publishes extensive guidelines outlining the procedures for per-forming carcinogenic and other types of risk assessments. GAO (1993) referred to this policy as “transparent” and noted that such detailed procedures were not yet readily available in the EU and other OECD countries surveyed. However, the specific guidance provided by the EPA may have the unintended effect of forcing risk assessment decisions (i.e., through the application of default assumptions) in ways not consistent with expert scientific judgement. The interviewees considered the U.S. process to be less flexible than the procedures used in other OECD countries, a fact they viewed as a weakness when compared to their system’s ability to flexibly address specific issues on a case-by-case basis (GAO, 1993). © 2001 by CRC Press LLC INTERNATIONAL HEALTH RISK ASSESSMENT APPROACHES FOR PESTICIDES 531 IV. PERFORMING ASSESSMENTS Two primary procedures exist for estimating the carcinogenic risks associated with exposure to pesticides (and other substances): mathematical models and ADIs. In general, quantitative risk assessment refers to the use of models since an actual risk value is calculated. This method is much more complex than the ADI approach in which the actual “risk” is presumed to be nonexistent. The ADI is derived from the highest dose in an animal study at which no adverse effects occur and is compared to the estimated human exposure. The U.S. typically employs models using sophisticated computer software to estimate cancer risk. The Netherlands is the only other country that regularly per-forms quantitative risk assessment utilizing such models, and it only uses these models for occupational exposures, not for pesticide assessments. Quantitative assessments using models are performed on a limited basis in Canada, Denmark, Germany, and the U.K., but again not for pesticides. In the U.S., the risk associated with carcinogenic substances is assessed using the linearized, multistage model. This model has two main constraints. First, it assumes no threshold for effects. In other words a single molecule of the pesti-cide/substance can induce the molecular events necessary to produce cancer (Barnes and Dourson, 1988). As a result, zero risk is only achieved when zero exposure occurs. Second, it assumes that the dose-response curve is linear in the low-dose region. This means that an increase in dose results in a proportional incremental increase in cancer risk. The decision to use this model was made in the 1970s and was based upon uncertainty regarding the shape of the dose-response curve in the nonexperimental, low-dose region. EPA believed that it was prudent to be conser-vative where the public was concerned and, thus, chose the linearized multistage model in order to provide the greatest protection. This model remains the default method for estimating the cancer risk of carcinogens. Alternative approaches may be implemented when the draft cancer risk assessment guidelines are formally adopted. As noted above, most countries rely on ADIs for establishing exposure limits for carcinogenic pesticides. These limits are not the same as risk values because they represent levels at which no risk is predicted to occur. ADIs are calculated by dividing the NOAEL or NOEL by Safety Factors (SF), also called uncertainty factors. These factors reflect the reliability and consistency of the experimental animal data. Generally, the more SFs applied the less confidence is placed in the data. The majority of the nations polled in the IPCS survey (Australia, Belgium, Bulgaria, Canada, China, Czechoslovakia, Denmark, France, Germany, India, Japan, Korea, The Netherlands, Spain, and the U.S.) routinely utilized the NOAEL/SF approach for estimating the risks associated with pesticide exposure (Dragula and Burin, 1994). As previously noted, the U.S. often uses quantitative models for estimating cancer risks. The reliance on the NOAEL/SF approach is easy to understand: it is simple to use and provides a clear, limit value below which exposures are considered accept-able. Although many countries currently rely on this approach for assessing cancer risks there are practical advantages to the risks calculated from quantitative models. © 2001 by CRC Press LLC ... - tailieumienphi.vn