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Toxicity and Safety Evaluation of Pesticides
Toxicity and Safety Evaluation of Pesticides Lindsay Hanson1 and Leonard Ritter2 1 2
Ottawa, Ontario, Canada School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada
Pesticide is a general term for a wide variety of products designed to control and manage pests. The term pests, at least in the context of a statutory or regulatory definition, extends to any unwanted or undesirable species. Common examples of pesticides and pests include herbicides to control weeds, insecticides to control insects, fungicides to control certain types of plant diseases, insect repellents, rodenticides to control rats, mice, gophers and other rodents, algicides to control algae in swimming pools, antifouling agents to control organisms that attach to boat hulls, and preservatives to control the decay of wood and other material. A pesticide may be a chemical or biological (e.g., bacteria and viruses used as pest control products) control agent. Pesticides differ from many other environmental substances of concern in that they enter the environment through intentional use for specified purposes. Ironically, it is the same biological effects that make pest control products valuable to society that may also result in unwanted effects that may pose risks to human and environmental health. Pesticide use in general, and some specific pesticide uses (landscape, for example), have emerged as the focus of one of the major public policy debates of our time. The use of chemical pesticides is certainly not, however, new. Stephenson and Solomon (2007) note that the use of chemical wastes to control roadside weeds was widely practiced by the Romans more than 2000 years ago. These authors also note that the development of inorganic chemicals as herbicides was under way in the 1800s and others, most notably fungicides to control plant diseases, followed. The dawn of the chemical era for pest control likely tracks its origins to the introduction in the 1930s of dinitrophenol, the first synthetic organic chemical for the control of weeds, insects, and plant diseases (Stephenson and Solomon, 2007). Rapid Hayes’ Handbook of Pesticide Toxicology Copyright © 2010 Elsevier Inc. All rights reserved
development followed in the 1940s and 1950s, with the synthesis of the insecticide dichlorodiphenyltrichloroethane (DDT), the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and the fungicide captan. Public concern over pesticide use followed soon thereafter. Indeed, in 1962 Rachel Carson, an accomplished naturalist, published her landmark book Silent Spring in which she highlighted important adverse environmental impacts attributable to the widespread use of the persistent organochlorine insecticides (Carson, 1962), most notably DDT, which, for many, was the metaphor for indiscriminate pesticide use. Interestingly, in 1948, only 14 years before Carson reported important adverse environmental effects associated with the indiscriminate use of DDT, the Swiss chemist Paul Müller had been awarded the Nobel Prize in Physiology or Medicine for his synthesis of DDT, which would be a critical turning point in the global fight against typhus and malaria. More than 40 years after Carson identified important environmental concerns related to the use of the persistent organochlorine insecticides, there is now renewed international interest in the reintroduction of DDT, under very carefully supervised conditions, for the control of the malaria vector (The National Academies Press, 2004). Web technology has made scientific information readily available to the general public with the click of a mouse. While this availability of information can generally be viewed as facilitating transparency and is generally positive, it is often difficult for the lay reader to place this information in the proper context. This is apparent in the daily reports of “Pesticide use linked to …,” often a serious health hazard. The general public more often asks why pesticides are being used and is concerned that exposures through diet or occupational or bystander scenarios are contributing to health problems. There is a general public perception that all 333
334
chemicals are dangerous, in particular the group known as pesticides. Robust scientific data are the basis for evidencebased health hazard assessment of the safety of pesticides and a cornerstone of regulatory programs. Pesticides, by their nature, have inherent hazards. They have been developed to control pests such as undesirable vegetation, insects, and fungi. Recognition of the need to carefully evaluate the potential risks to human health from pesticide use, when considered together with the potential benefit, is why countries around the world have developed rigorous pesticide regulatory programs. Canada and the United States, for example, use similar science-based approaches, entrenched in legislation, for human health risk assessment dealing with pesticides. This framework for the risk assessment of pesticides is well accepted internationally (International Programme on Chemical Safety, 1999) and consists of four key activities: hazard identification, hazard characterization, exposure assessment, and risk characterization. Toxicological evaluation involves identifying possible human health effects related to pesticide exposures and establishing levels of human exposure that would not result in adverse effects. As a starting point, a robust data set consisting of an extensive battery of toxicity studies, conducted primarily in laboratory animals, is required to identify and characterize the hazard potential posed by pesticides. These studies are typically carried out on a variety of mammalian species (rats, mice, rabbits, dogs). Hazard identification involves understanding the inherent toxicological properties of a chemical substance. This understanding is gained through the conduct of toxicity studies that will address both the duration of exposure (acute, short-term, or chronic) and the different routes of exposure (oral, dermal, and inhalation). Various endpoints of toxicity (reproductive toxicity, developmental toxicity, genotoxicity, chronic toxicity and carcinogenicity, neurotoxicity, immunotoxicity, etc.) will be assessed to fully identify the hazards posed by chemical pesticides (Health Canada, 2008). Manufacturers of pesticides in all of the Organization of Economic Co-operation and Development (OECD) countries are required to demonstrate the safety of their products, to both human health and the environment, and are responsible to carry out the requisite studies. These are conducted according to internationally accepted Test Guidelines under Good Laboratory Practices (GLP). Generally, the test substance used in toxicity testing will be the quality grade of the active ingredient that is produced during typical manufacturing processes, often identified as the “technical” grade of the compound. A number of studies with the actual end-use formulated product (marketed pesticide), which includes the solvents, adjuvants, and carriers, are also required for purposes of developing hazard label statements for each pesticide. It is essential that all toxicology studies identify the test material used in each study.
Hayes’ Handbook of Pesticide Toxicology
I.1 Health hazard evaluation—role in the assessment of pesticide risks to humans Hazard characterization involves defining the relationship between the dose of a chemical administered to or received by the test species and the qualitative and quantitative response to that chemical (Health Canada, 2008). It is generally assumed that there is a dose level below which the chemical will not elicit a response, that is, there is a threshold for the response. “Most responses elicited by a substance, including acute toxicity, chronic toxicity, neurotoxicity, irritation, developmental toxicity, and reproductive toxicity, are considered threshold in nature. Endpoints that have been observed to lack a threshold response (e.g., genotoxicity, carcinogenicity) are assumed to result in an increase in risk at any level of exposure and hence are subject to different risk assessment methodologies” (Health Canada, 2008). The experimental dose level at which no adverse effects are detected in a given study is deemed the no observed adverse effect level (NOAEL). The lowest dose level in a study that elicits an adverse effect is referred to as the lowest observed adverse effect level (LOAEL). An adverse effect is commonly defined as “a change in morphology, physiology, growth, development or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increase in susceptibility to the harmful effects of other environmental influences” (International Programme on Chemical Safety, 1994). Determination of a true adverse effect is not always straightforward; “expert judgment is required to separate those effects that merely reflect the ability of an organism to adapt to a biological or chemical insult from a true adverse effect”. (Health Canada, 2008) “The evaluation of a mammalian toxicological database for a specific pesticide will yield numerous NOAELs for different toxicological endpoints. The selection of the most appropriate study, endpoint, and NOAEL for human health risk assessment takes into consideration which human subpopulations may be exposed, the route of exposure, and the anticipated duration and/or frequency of exposure”. (Health Canada, 2008) Although a comprehensive scientific database is available for most pesticides, one cannot prove scientifically that something is safe with absolute certainty. The general public increasingly demands assurances of safety with respect to chemical exposure. A rigorous pesticide regulatory system begins with sound scientific data.
I.������� 2 Toxicokinetic studies Toxicokinetic studies provide data on the absorption, distribution, metabolism, and excretion (ADME) of the chemical pesticide. In general terms, how does it enter the body,
Toxicity and Safety Evaluation of Pesticides
where does it go, and what happens to it? These studies will also provide information on other parameters of interest, including differences between small and large doses, and single versus multiple exposures. “This information is valuable in interpreting toxic effects, or lack thereof, and may assist in the extrapolation of animal toxicity data to humans” (Health Canada, 2005). Understanding the toxicokinetics of the pesticide may also enable more appropriate selection of doses and routes of administration used in many of the laboratory studies. Generally speaking, the use pattern and physical properties of the product, as well as toxicokinetic considerations, will assist in determining the appropriate route of exposure and duration of study.
I.������� 3 Acute toxicity studies Acute toxicity studies on active ingredients and end-use formulated pesticide products are necessary to determine the potential hazards from acute exposures. These studies are typically characterized by a high dose in a short time frame. Acute data are used for the development of appropriate precautionary statements and hazard symbols for pesticide product labels. Acute studies identify relative acute toxicities by different routes of exposure as well as the potential to produce irritation and sensitization (Health Canada, 2005).
I.������� 4 Short-term studies Short-term or subchronic studies provide information on the toxicity profile of the pesticide through daily repeated exposure often over a period of weeks or months depending on the animal species. Guidelines for short-term studies set the dosing period for a duration lasting up to 10% of the animal’s life span. This is often defined as 90 days in rats and mice, or 1 year in dogs. The data obtained from these short-term studies are useful in determining possible cumulative or delayed toxicity, reversibility and persistence of the adverse effect, and variability in species sensitivity. These studies also provide guidance for selecting dose levels for long-term studies.
I.������� 5 Long-term studies “Long-term daily repeated exposure studies are generally designed to investigate the chronic toxicity and oncogenic potential of the pesticide when administered to test animals over the major portion of their life span” (Health Canada, 2005); by convention, chronic toxicity and oncogenicity studies must include exposure periods of at least 90% of the anticipated life span of the test animal—interpreted to be 24 months duration in rats and 18 months in mice. Ideally, the data thus generated should identify dose—response relationships and, in the case of nononcogenic effects, a clear
335
demonstration of a dose that is not associated with any adverse effect (the NOAEL) and possible effects of cumulative toxicity as well as permit assessment of the potential for neoplastic development (Health Canada, 2005).
I.������� 6 Reproduction studies “These studies provide information on the potential of the pesticide to influence the reproductive performance and function of the male and female parental animals, through assessment of effects on gonadal function, estrus cycles, mating behavior, conception, parturition, lactation, and weaning. Observation of progeny from conception through lactation and weaning may enable the detection of possible adverse effects on survival, viability, development, and behavior. These studies have a pivotal role in determining the potential sensitivity of the young animal” (Health Canada, 2005).
I.������� 7 Developmental toxicity studies “These studies, referred to in the past as teratogenicity studies, permit assessment of the potential of the pesticide to induce adverse effects on the developing embryo and fetus when administered to the pregnant female test animal during critical periods of organogenesis. Studies are generally conducted in a rodent and a nonrodent species. The teratogenic potential of the pesticide may be measured by the increased incidence or induction of congenital malformations. These studies also have a pivotal role in determining the potential increased sensitivity of the young animal” (Health Canada, 2005).
I.������� 8 Genotoxicity/mutagenicity studies Tests for genetic damage are designed to assess both gene mutations and chromosomal changes as well as the competency of DNA repair mechanisms. Genotoxicity studies can also be very helpful in determining and understanding carcinogenic potential (Health Canada, 2005).
I.������� 9 Neurotoxicity and developmental neurotoxicity studies “The neurotoxic potential of the pesticide may be assessed on the basis of behavior, neurophysiology, neurochemistry, and neuropathology. Neurotoxicity screening tests may be incorporated into several of the standard protocols for acute toxicity as well as short- and long-term repeated exposure toxicity studies. This may be accomplished through expanded histopathological examination of the brain, spinal
Hayes’ Handbook of Pesticide Toxicology
336
cord, and peripheral nervous system, a functional observational battery of tests for general behavior and neurology, as well as autonomic and sensory assessment. Appropriate tests may also be incorporated into the standard protocol for reproduction studies for the purpose of assessing the neurotoxic potential of the pesticide in the progeny” (Health Canada, 2005). Developmental neurotoxicity (DNT) studies may also be required for specific pesticides where enhanced sensitivity to the effects of the chemical has been observed in young animals. Further testing may be appropriate for pesticides known or suspected to be neurotoxicants.
I.�������� 10 Immunotoxicity “The potential of the pesticide to affect the immune system may be discerned from hematology, blood chemistry, organ weights, and histopathology, routinely investigated in shortterm and chronic toxicity studies” (Health Canada, 2005). Specific aspects of the immune response, or elucidation of immunomodulation mechanisms, may be investigated through additional assays to help predict a chemically induced functional effect on the immune system. “These assays may be considered to further investigate lymphocyte subsets, humoral antibody-mediated immunity, as well as cell-mediated and nonspecific immunity” (Health Canada, 2005).
I.�������� 11 Endocrine disruptor potential Endocrine disruptor potential (such as interference with the production of sex hormones) is evaluated in the course of examining the information from reproduction, developmental, and short- and long-term toxicity studies. If the results of these studies indicate the need for further information regarding interference with normal endocrine function, additional testing may be required.
I.�������� 12 Mechanism of action “Ancillary studies designed to elucidate specific mechanisms of action in the test animal may be key in interpreting the toxicological properties of the pesticide” (Health Canada, 2005). Such information may permit a more appropriate assessment of the relevance of the animal studies, and potential adverse health effects identified therein, to an understanding of health hazards (Health Canada, 2005).
Conclusion The importance of a robust data set when regulating a chemical substance such as a pesticide cannot be overstated. The general public, with instant access to emerging science from around the globe, must be confident in their regulatory environment. Regulatory bodies must be keenly aware of evolving science and the questions raised by those emerging issues. They must continue to recognize and adapt to the requirements of comprehensive studies from industry to address these questions. Industry must be prepared to meet these demands if they look to address public concerns. Risk communication in an open and transparent environment will be key to building public confidence. All users of pesticides must be made aware of the importance of following label directions and heeding precautionary statements. A complete and comprehensive set of toxicological studies will provide the cornerstone for building that trust.
References Carson, R. (1962). “Silent Spring,”. Houghton Mifflin, Boston, MA. International Programme on Chemical Safety. (1994). Environmental Health Criteria 170. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health-Based Exposure Limits. Geneva, Switzerland, World Health Organization, International Programme on Chemical Safety. www.inchem.org/documents/ehc/ ehc/ehc170.htm International Programme on Chemical Safety. (1999). Environmental Health Criteria 210. Principles for theAssessment of Risks to Human Health from Exposure to Chemicals. Geneva, Switzerland, World Health Organization, International Programme on Chemical Safety. www.inchem.org/documents/ehc/ehc/ehc210.htm Health Canada (2005). “Pest Management Regulatory Agency Regulatory Directive DIR2005-01: Guidelines for Developing a Toxicological Database for Chemical Pest Control Products”. Health Canada Ottawa. Health Canada (2008). “Pest Management Regulatory Agency Science Policy Note SPN2008-01. The Application of Uncertainty Factors and the Pest Control Products Act Factor in the Human Health Risk Assessment of Pesticides”. Health Canada, Ottawa. Stephenson, G. R. and Solomon, K. R. (2007). “Pesticides in the Environment,”. Canadian Network of Toxicology Centres Press, Guelph, Canada. The National Academies Press (2004). Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Board on Global Health, The National Academies Press.
Ottawa, Ontario, Canada School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada
Pesticide is a general term for a wide variety of products designed to control and manage pests. The term pests, at least in the context of a statutory or regulatory definition, extends to any unwanted or undesirable species. Common examples of pesticides and pests include herbicides to control weeds, insecticides to control insects, fungicides to control certain types of plant diseases, insect repellents, rodenticides to control rats, mice, gophers and other rodents, algicides to control algae in swimming pools, antifouling agents to control organisms that attach to boat hulls, and preservatives to control the decay of wood and other material. A pesticide may be a chemical or biological (e.g., bacteria and viruses used as pest control products) control agent. Pesticides differ from many other environmental substances of concern in that they enter the environment through intentional use for specified purposes. Ironically, it is the same biological effects that make pest control products valuable to society that may also result in unwanted effects that may pose risks to human and environmental health. Pesticide use in general, and some specific pesticide uses (landscape, for example), have emerged as the focus of one of the major public policy debates of our time. The use of chemical pesticides is certainly not, however, new. Stephenson and Solomon (2007) note that the use of chemical wastes to control roadside weeds was widely practiced by the Romans more than 2000 years ago. These authors also note that the development of inorganic chemicals as herbicides was under way in the 1800s and others, most notably fungicides to control plant diseases, followed. The dawn of the chemical era for pest control likely tracks its origins to the introduction in the 1930s of dinitrophenol, the first synthetic organic chemical for the control of weeds, insects, and plant diseases (Stephenson and Solomon, 2007). Rapid Hayes’ Handbook of Pesticide Toxicology Copyright © 2010 Elsevier Inc. All rights reserved
development followed in the 1940s and 1950s, with the synthesis of the insecticide dichlorodiphenyltrichloroethane (DDT), the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and the fungicide captan. Public concern over pesticide use followed soon thereafter. Indeed, in 1962 Rachel Carson, an accomplished naturalist, published her landmark book Silent Spring in which she highlighted important adverse environmental impacts attributable to the widespread use of the persistent organochlorine insecticides (Carson, 1962), most notably DDT, which, for many, was the metaphor for indiscriminate pesticide use. Interestingly, in 1948, only 14 years before Carson reported important adverse environmental effects associated with the indiscriminate use of DDT, the Swiss chemist Paul Müller had been awarded the Nobel Prize in Physiology or Medicine for his synthesis of DDT, which would be a critical turning point in the global fight against typhus and malaria. More than 40 years after Carson identified important environmental concerns related to the use of the persistent organochlorine insecticides, there is now renewed international interest in the reintroduction of DDT, under very carefully supervised conditions, for the control of the malaria vector (The National Academies Press, 2004). Web technology has made scientific information readily available to the general public with the click of a mouse. While this availability of information can generally be viewed as facilitating transparency and is generally positive, it is often difficult for the lay reader to place this information in the proper context. This is apparent in the daily reports of “Pesticide use linked to …,” often a serious health hazard. The general public more often asks why pesticides are being used and is concerned that exposures through diet or occupational or bystander scenarios are contributing to health problems. There is a general public perception that all 333
334
chemicals are dangerous, in particular the group known as pesticides. Robust scientific data are the basis for evidencebased health hazard assessment of the safety of pesticides and a cornerstone of regulatory programs. Pesticides, by their nature, have inherent hazards. They have been developed to control pests such as undesirable vegetation, insects, and fungi. Recognition of the need to carefully evaluate the potential risks to human health from pesticide use, when considered together with the potential benefit, is why countries around the world have developed rigorous pesticide regulatory programs. Canada and the United States, for example, use similar science-based approaches, entrenched in legislation, for human health risk assessment dealing with pesticides. This framework for the risk assessment of pesticides is well accepted internationally (International Programme on Chemical Safety, 1999) and consists of four key activities: hazard identification, hazard characterization, exposure assessment, and risk characterization. Toxicological evaluation involves identifying possible human health effects related to pesticide exposures and establishing levels of human exposure that would not result in adverse effects. As a starting point, a robust data set consisting of an extensive battery of toxicity studies, conducted primarily in laboratory animals, is required to identify and characterize the hazard potential posed by pesticides. These studies are typically carried out on a variety of mammalian species (rats, mice, rabbits, dogs). Hazard identification involves understanding the inherent toxicological properties of a chemical substance. This understanding is gained through the conduct of toxicity studies that will address both the duration of exposure (acute, short-term, or chronic) and the different routes of exposure (oral, dermal, and inhalation). Various endpoints of toxicity (reproductive toxicity, developmental toxicity, genotoxicity, chronic toxicity and carcinogenicity, neurotoxicity, immunotoxicity, etc.) will be assessed to fully identify the hazards posed by chemical pesticides (Health Canada, 2008). Manufacturers of pesticides in all of the Organization of Economic Co-operation and Development (OECD) countries are required to demonstrate the safety of their products, to both human health and the environment, and are responsible to carry out the requisite studies. These are conducted according to internationally accepted Test Guidelines under Good Laboratory Practices (GLP). Generally, the test substance used in toxicity testing will be the quality grade of the active ingredient that is produced during typical manufacturing processes, often identified as the “technical” grade of the compound. A number of studies with the actual end-use formulated product (marketed pesticide), which includes the solvents, adjuvants, and carriers, are also required for purposes of developing hazard label statements for each pesticide. It is essential that all toxicology studies identify the test material used in each study.
Hayes’ Handbook of Pesticide Toxicology
I.1 Health hazard evaluation—role in the assessment of pesticide risks to humans Hazard characterization involves defining the relationship between the dose of a chemical administered to or received by the test species and the qualitative and quantitative response to that chemical (Health Canada, 2008). It is generally assumed that there is a dose level below which the chemical will not elicit a response, that is, there is a threshold for the response. “Most responses elicited by a substance, including acute toxicity, chronic toxicity, neurotoxicity, irritation, developmental toxicity, and reproductive toxicity, are considered threshold in nature. Endpoints that have been observed to lack a threshold response (e.g., genotoxicity, carcinogenicity) are assumed to result in an increase in risk at any level of exposure and hence are subject to different risk assessment methodologies” (Health Canada, 2008). The experimental dose level at which no adverse effects are detected in a given study is deemed the no observed adverse effect level (NOAEL). The lowest dose level in a study that elicits an adverse effect is referred to as the lowest observed adverse effect level (LOAEL). An adverse effect is commonly defined as “a change in morphology, physiology, growth, development or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increase in susceptibility to the harmful effects of other environmental influences” (International Programme on Chemical Safety, 1994). Determination of a true adverse effect is not always straightforward; “expert judgment is required to separate those effects that merely reflect the ability of an organism to adapt to a biological or chemical insult from a true adverse effect”. (Health Canada, 2008) “The evaluation of a mammalian toxicological database for a specific pesticide will yield numerous NOAELs for different toxicological endpoints. The selection of the most appropriate study, endpoint, and NOAEL for human health risk assessment takes into consideration which human subpopulations may be exposed, the route of exposure, and the anticipated duration and/or frequency of exposure”. (Health Canada, 2008) Although a comprehensive scientific database is available for most pesticides, one cannot prove scientifically that something is safe with absolute certainty. The general public increasingly demands assurances of safety with respect to chemical exposure. A rigorous pesticide regulatory system begins with sound scientific data.
I.������� 2 Toxicokinetic studies Toxicokinetic studies provide data on the absorption, distribution, metabolism, and excretion (ADME) of the chemical pesticide. In general terms, how does it enter the body,
Toxicity and Safety Evaluation of Pesticides
where does it go, and what happens to it? These studies will also provide information on other parameters of interest, including differences between small and large doses, and single versus multiple exposures. “This information is valuable in interpreting toxic effects, or lack thereof, and may assist in the extrapolation of animal toxicity data to humans” (Health Canada, 2005). Understanding the toxicokinetics of the pesticide may also enable more appropriate selection of doses and routes of administration used in many of the laboratory studies. Generally speaking, the use pattern and physical properties of the product, as well as toxicokinetic considerations, will assist in determining the appropriate route of exposure and duration of study.
I.������� 3 Acute toxicity studies Acute toxicity studies on active ingredients and end-use formulated pesticide products are necessary to determine the potential hazards from acute exposures. These studies are typically characterized by a high dose in a short time frame. Acute data are used for the development of appropriate precautionary statements and hazard symbols for pesticide product labels. Acute studies identify relative acute toxicities by different routes of exposure as well as the potential to produce irritation and sensitization (Health Canada, 2005).
I.������� 4 Short-term studies Short-term or subchronic studies provide information on the toxicity profile of the pesticide through daily repeated exposure often over a period of weeks or months depending on the animal species. Guidelines for short-term studies set the dosing period for a duration lasting up to 10% of the animal’s life span. This is often defined as 90 days in rats and mice, or 1 year in dogs. The data obtained from these short-term studies are useful in determining possible cumulative or delayed toxicity, reversibility and persistence of the adverse effect, and variability in species sensitivity. These studies also provide guidance for selecting dose levels for long-term studies.
I.������� 5 Long-term studies “Long-term daily repeated exposure studies are generally designed to investigate the chronic toxicity and oncogenic potential of the pesticide when administered to test animals over the major portion of their life span” (Health Canada, 2005); by convention, chronic toxicity and oncogenicity studies must include exposure periods of at least 90% of the anticipated life span of the test animal—interpreted to be 24 months duration in rats and 18 months in mice. Ideally, the data thus generated should identify dose—response relationships and, in the case of nononcogenic effects, a clear
335
demonstration of a dose that is not associated with any adverse effect (the NOAEL) and possible effects of cumulative toxicity as well as permit assessment of the potential for neoplastic development (Health Canada, 2005).
I.������� 6 Reproduction studies “These studies provide information on the potential of the pesticide to influence the reproductive performance and function of the male and female parental animals, through assessment of effects on gonadal function, estrus cycles, mating behavior, conception, parturition, lactation, and weaning. Observation of progeny from conception through lactation and weaning may enable the detection of possible adverse effects on survival, viability, development, and behavior. These studies have a pivotal role in determining the potential sensitivity of the young animal” (Health Canada, 2005).
I.������� 7 Developmental toxicity studies “These studies, referred to in the past as teratogenicity studies, permit assessment of the potential of the pesticide to induce adverse effects on the developing embryo and fetus when administered to the pregnant female test animal during critical periods of organogenesis. Studies are generally conducted in a rodent and a nonrodent species. The teratogenic potential of the pesticide may be measured by the increased incidence or induction of congenital malformations. These studies also have a pivotal role in determining the potential increased sensitivity of the young animal” (Health Canada, 2005).
I.������� 8 Genotoxicity/mutagenicity studies Tests for genetic damage are designed to assess both gene mutations and chromosomal changes as well as the competency of DNA repair mechanisms. Genotoxicity studies can also be very helpful in determining and understanding carcinogenic potential (Health Canada, 2005).
I.������� 9 Neurotoxicity and developmental neurotoxicity studies “The neurotoxic potential of the pesticide may be assessed on the basis of behavior, neurophysiology, neurochemistry, and neuropathology. Neurotoxicity screening tests may be incorporated into several of the standard protocols for acute toxicity as well as short- and long-term repeated exposure toxicity studies. This may be accomplished through expanded histopathological examination of the brain, spinal
Hayes’ Handbook of Pesticide Toxicology
336
cord, and peripheral nervous system, a functional observational battery of tests for general behavior and neurology, as well as autonomic and sensory assessment. Appropriate tests may also be incorporated into the standard protocol for reproduction studies for the purpose of assessing the neurotoxic potential of the pesticide in the progeny” (Health Canada, 2005). Developmental neurotoxicity (DNT) studies may also be required for specific pesticides where enhanced sensitivity to the effects of the chemical has been observed in young animals. Further testing may be appropriate for pesticides known or suspected to be neurotoxicants.
I.�������� 10 Immunotoxicity “The potential of the pesticide to affect the immune system may be discerned from hematology, blood chemistry, organ weights, and histopathology, routinely investigated in shortterm and chronic toxicity studies” (Health Canada, 2005). Specific aspects of the immune response, or elucidation of immunomodulation mechanisms, may be investigated through additional assays to help predict a chemically induced functional effect on the immune system. “These assays may be considered to further investigate lymphocyte subsets, humoral antibody-mediated immunity, as well as cell-mediated and nonspecific immunity” (Health Canada, 2005).
I.�������� 11 Endocrine disruptor potential Endocrine disruptor potential (such as interference with the production of sex hormones) is evaluated in the course of examining the information from reproduction, developmental, and short- and long-term toxicity studies. If the results of these studies indicate the need for further information regarding interference with normal endocrine function, additional testing may be required.
I.�������� 12 Mechanism of action “Ancillary studies designed to elucidate specific mechanisms of action in the test animal may be key in interpreting the toxicological properties of the pesticide” (Health Canada, 2005). Such information may permit a more appropriate assessment of the relevance of the animal studies, and potential adverse health effects identified therein, to an understanding of health hazards (Health Canada, 2005).
Conclusion The importance of a robust data set when regulating a chemical substance such as a pesticide cannot be overstated. The general public, with instant access to emerging science from around the globe, must be confident in their regulatory environment. Regulatory bodies must be keenly aware of evolving science and the questions raised by those emerging issues. They must continue to recognize and adapt to the requirements of comprehensive studies from industry to address these questions. Industry must be prepared to meet these demands if they look to address public concerns. Risk communication in an open and transparent environment will be key to building public confidence. All users of pesticides must be made aware of the importance of following label directions and heeding precautionary statements. A complete and comprehensive set of toxicological studies will provide the cornerstone for building that trust.
References Carson, R. (1962). “Silent Spring,”. Houghton Mifflin, Boston, MA. International Programme on Chemical Safety. (1994). Environmental Health Criteria 170. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health-Based Exposure Limits. Geneva, Switzerland, World Health Organization, International Programme on Chemical Safety. www.inchem.org/documents/ehc/ ehc/ehc170.htm International Programme on Chemical Safety. (1999). Environmental Health Criteria 210. Principles for theAssessment of Risks to Human Health from Exposure to Chemicals. Geneva, Switzerland, World Health Organization, International Programme on Chemical Safety. www.inchem.org/documents/ehc/ehc/ehc210.htm Health Canada (2005). “Pest Management Regulatory Agency Regulatory Directive DIR2005-01: Guidelines for Developing a Toxicological Database for Chemical Pest Control Products”. Health Canada Ottawa. Health Canada (2008). “Pest Management Regulatory Agency Science Policy Note SPN2008-01. The Application of Uncertainty Factors and the Pest Control Products Act Factor in the Human Health Risk Assessment of Pesticides”. Health Canada, Ottawa. Stephenson, G. R. and Solomon, K. R. (2007). “Pesticides in the Environment,”. Canadian Network of Toxicology Centres Press, Guelph, Canada. The National Academies Press (2004). Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Board on Global Health, The National Academies Press.