- Email: [email protected]
Use of mechanistic and pharmacokinetic data for risk assessment at the National Institute of Environmental Health Sciences (NIEHS)
l6xkology
letters
ELSEVIER
Toxicology
Letters
79 (1995) 29-32
Use of mechanistic and pharmacokinetic data for risk assessment at the National Institute of Environmental Health Sciences (NIEHS) B.A. Schwetz Director, National Cenrer for Toxicological Research, 3900 NCTR Road, Bldg. 13, JefSerson, AR 72079-9502, Accepted
5 April
USA
1995
Abstract In summary, the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP) have been important contributors of data for hazard identification, including toxicological data as well as mechanistic and pharmacokinetic information. One of the factors that limits the use of knowledge is our lack of understanding of the animal test models currently in use. The underlying bases for regulatory controls that account for normal physiological functions are often not well understood. As a result, toxicological data tend to be used in an empirical manner rather than a manner based on mechanistic understanding. Continued testing of chemicals and random generation of data have their limits in improving our predictive abilities. Attention must be given to prioritizing studies on the basis of critical gaps in understanding that are needed to build knowledge bases in the future. Keywords:
Toxicity studies; Pharmacokinetic
studies; Knowledge bases
The hazard identification component of the National Institute of Environmental Health Sciences (NIEHS) is the National Toxicology Program (NTP). This program was started in 1978 and continues today to be a major source of toxicological data for regulatory and public health decisions worldwide. The major objectives of the NTP have been to chara.cterize the toxicity of chemicals and other substances, as well as to develop, refine, and validate improved methods for characterizing the toxicity of substances of concern. In addition to toxicological testing to identify various types of 0378-4274/95/$09.50
Elsevier
SSDI 0378-4274(95)03354-N
Science Ireland
Ltd.
toxicity, a considerable effort of the NTP involves the development of mechanistic data, including data to describe the disposition and pharmacokinetic profile of chemicals, primarily those being studied for toxicological properties by the Program.
1. Characterization
of toxicity
The approach used by the NTP to characterize the toxicity of chemicals and other agents serves
30
B.A. Schwetz
1 Toxicology
as a model for such efforts worldwide. The data that result from testing by the NTP have been used for major risk decisions by all major regulatory and advisory bodies. Depending on the availability of information in the literature, the profile of toxicity data that is frequently developed by the NTP includes genetic toxicity data to characterize the potential of the agent to be a carcinogen through genetic mechanisms, and to identify the potential of the agent to cause genetic toxicity beyond the question of carcinogenic potential. Studies of the disposition of the chemical are frequently done prior to further toxicological testing to characterize the extent of absorption of the agent by relevant routes of exposure and to develop the correlation between blood level and exposure. In addition, disposition studies are done to determine the linearity of the blood level vs. dose curve over the anticipated range of exposure for toxicological testing. Subchronic toxicity studies are conducted to characterize the profile of target organ toxicity, the dose-response curve for the toxicities observed, and to compare toxicity between genders and between rats and mice. Toxicokinetic studies are an integral part of the subchronic toxicity studies to correlate blood levels with toxicity. The NTP conducts reproductive toxicity studies on many of the chemicals that are nominated for testing by the Program. This includes measures of effects on fertility and reproductive performance using a continuous breeding protocol. Other studies are conducted to determine the potential of agents to cause developmental toxicity following exposure of pregnant females. Studies are also done to evaluate the potential of chemicals to cause germ cell damage. Other systemic toxicities are tested, including potential effects on the function of the immune system and the nervous system. Toxicity to other organ systems is characterized, depending on the observations that are made in the subchronic toxicity studies. Carcinogenicity and chronic toxicity studies are conducted in rats and mice. As a sequel to this series of toxicological studies, additional studies of metabolism and pharmacokinetics are often conducted to help explain the nature of the toxicities that are observed, to better
Letters
79 (1995) 29-32
identify metabolites that might account for the toxicities, and to develop data to explain observed differences in gender responses, differences between the species or between routes of exposure. Other mechanistic studies are done to facilitate the final interpretation of the toxicological data. Examples of chemicals of major commercial importance that have been the subject of such toxicological investigation by the NTP include 1,3-butadiene, benzene, methylene chloride, and boric acid. Extensive studies of the metabolism and pharmacokinetics of butadiene were conducted to identify the metabolite which might account for the carcinogenic potential and to explain the significant difference in sensitivity between rats and mice. Extensive pharmacokinetic studies were conducted on benzene to better understand the metabolites which account for the observed carcinogenicity and to explain species differences in sensitivity. The NTP reported carcinogenic effects following inhalation of methylene chloride by mice. A significant increase in tumors of the lung and liver were reported. Studies were conducted to better understand the mechanisms by which methylene chloride caused these tumors in mice and to explain the importance of changes in cell replication as they might be causally related to the carcinogenic potential. Studies were also conducted to assess the two major metabolic profiles of methylene chloride and their relative contribution to the carcinogenicity. Boric acid has been confirmed as a reproductive and developmental toxicant in laboratory species by the NTP. A series of studies has been conducted to try to understand the mechanism by which boric acid might cause infertility in males, including investigations of target site dosimetry, genetic damage, and effects of cellular metabolism. In these and other cases, the NTP strives to characterize the toxicity of chemicals by integrating the knowledge from a range of studies. Data from specific responses are interpreted on the basis of the total body of data available. Two major workshops held during 1993 reinforced the importance of using bodies of knowledge to better predict toxicity. A workshop was held in March, 1993, to compare the predictiveness of carcino-
B.A. Schwerz 1 Toxicology Letters 79 (1995) 29-32
genicity induced b:y chemicals using systems developed by various investigators throughout the country. Predictions were sought regarding the outcome of more than 40 2-year carcinogenicity studies that were being conducted by the NTP. Upon the conclusion of the 2-year studies, this workshop was held to compare the predictiveness of the systems used by the various investigators. Such workshops help to identify shortcomings of predictive systems, and lead to refinements that will, hopefully, improve the predictiveness for carcinogenic potential. Another workshop held in November of 1993, sponsored by the United States Environmental Protection Agency (EPA), was held to evaluate the potential usefulness of benchmark doses as an approach for risk assessment of developmental toxicity studies and other manifestations of toxicity for which there are thresholds. A large portion of the data analyzed in this workshop was the results of NTP developmental toxicity studies. Workshops such as these are important steps in the process of improving the use of our toxicological data to predict potential hazards for human exposure. 2. Methods development The NTP has traditionally been a major contributor in the area of developing and refining toxicological test methods in all areas of toxicological testing. h4ajor contributions have been made in the area of genetic toxicity tests, carcinogenicity studies, reproductive and developmental toxicity studies, immunotoxicity, and neurotoxicity studies. Recently, a significant emphasis has been placed on t’he development of screens that use alternative systems and species, or in vitro systems. Efforts to develop alternative approaches are very important from the standpoint of developing better test methods, especially methods that minimize our dependence on the use of higher species of animals for toxicological testing. These systems, if effective, would also be more cost effective than extensive toxicological testing using large numbers of higher species. It is important to recognize, however, that approaches using in vitro systems or alternaitive species are a stop-gap measure to the goal for predicting toxicity and haz-
31
ard. The development of alternative approaches is a reasonable step to decrease our dependence on whole animal testing, but it is not the eventual goal that we have as scientists for being able to predict toxicity. The ultimate goal of predictive systems would be the development of knowledge bases that would permit us to develop answers to questions on the basis of information in the knowledge base without having to conduct animal studies to generate information on a screening basis. Animal studies might be done to confirm predictions from the knowledge base, but the knowledge base itself would be the basis of the estimates of toxicity and hazard. Efforts to develop such knowledge bases have not been highly successful, although they are more successful in some manifestations of toxicity than others. Knowledge bases, as opposed to databases, do not exist for most manifestations of toxicity today because we do not have enough information to build the knowledge bases. We continue to test chemicals singly or within structural families, but the knowledge is not adequate to be able to predict the toxicity of chemicals that are outside of a few chemical or pharmacological families. The process of generating information that has characterized our toxicology efforts over the last several decades is inefficient in producing knowledge bases that would preclude the need for additional routine testing. What we have learned from the random process of testing chemicals has reached an educational plateau and, while it meets the needs of having data on individual chemicals, large increments in knowledge do not happen from random testing of chemicals. In addition, support of basic biomedical research is also done on the basis of good science, a random process, rather than a well-defined strategy of research to develop certain knowledge to build knowledge bases. As a result, we do not have knowledge bases consisting of toxicological and other biological and chemical data that permit us to predict the toxicity of chemicals or other substances in the environment. To develop knowledge bases, we must develop a strategy for collecting the priority data needed to build knowledge bases. This would most effectively be done for those endpoints of toxicity where we have extensive knowledge from
32
B.A. Schetr
/ Toxicology Letters 79 (1995) 29-32
prior testing and understanding about mechanisms of toxicity. With such knowledge bases in hand, animal studies might be limited to confirmation of those biological properties that are predicted from the computerized knowledge bases or from other non-laboratory systems. Metabolism and pharmacokinetic data would obviously be a very important
component of these knowledge bases. Approaches such as physiologically based pharmacokinetic modeling would be important for answering such questions as the extrapolation between species and across routes of exposure, and to provide a basis for predicting levels of exposure at which some hazard might exist.
letters
ELSEVIER
Toxicology
Letters
79 (1995) 29-32
Use of mechanistic and pharmacokinetic data for risk assessment at the National Institute of Environmental Health Sciences (NIEHS) B.A. Schwetz Director, National Cenrer for Toxicological Research, 3900 NCTR Road, Bldg. 13, JefSerson, AR 72079-9502, Accepted
5 April
USA
1995
Abstract In summary, the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP) have been important contributors of data for hazard identification, including toxicological data as well as mechanistic and pharmacokinetic information. One of the factors that limits the use of knowledge is our lack of understanding of the animal test models currently in use. The underlying bases for regulatory controls that account for normal physiological functions are often not well understood. As a result, toxicological data tend to be used in an empirical manner rather than a manner based on mechanistic understanding. Continued testing of chemicals and random generation of data have their limits in improving our predictive abilities. Attention must be given to prioritizing studies on the basis of critical gaps in understanding that are needed to build knowledge bases in the future. Keywords:
Toxicity studies; Pharmacokinetic
studies; Knowledge bases
The hazard identification component of the National Institute of Environmental Health Sciences (NIEHS) is the National Toxicology Program (NTP). This program was started in 1978 and continues today to be a major source of toxicological data for regulatory and public health decisions worldwide. The major objectives of the NTP have been to chara.cterize the toxicity of chemicals and other substances, as well as to develop, refine, and validate improved methods for characterizing the toxicity of substances of concern. In addition to toxicological testing to identify various types of 0378-4274/95/$09.50
Elsevier
SSDI 0378-4274(95)03354-N
Science Ireland
Ltd.
toxicity, a considerable effort of the NTP involves the development of mechanistic data, including data to describe the disposition and pharmacokinetic profile of chemicals, primarily those being studied for toxicological properties by the Program.
1. Characterization
of toxicity
The approach used by the NTP to characterize the toxicity of chemicals and other agents serves
30
B.A. Schwetz
1 Toxicology
as a model for such efforts worldwide. The data that result from testing by the NTP have been used for major risk decisions by all major regulatory and advisory bodies. Depending on the availability of information in the literature, the profile of toxicity data that is frequently developed by the NTP includes genetic toxicity data to characterize the potential of the agent to be a carcinogen through genetic mechanisms, and to identify the potential of the agent to cause genetic toxicity beyond the question of carcinogenic potential. Studies of the disposition of the chemical are frequently done prior to further toxicological testing to characterize the extent of absorption of the agent by relevant routes of exposure and to develop the correlation between blood level and exposure. In addition, disposition studies are done to determine the linearity of the blood level vs. dose curve over the anticipated range of exposure for toxicological testing. Subchronic toxicity studies are conducted to characterize the profile of target organ toxicity, the dose-response curve for the toxicities observed, and to compare toxicity between genders and between rats and mice. Toxicokinetic studies are an integral part of the subchronic toxicity studies to correlate blood levels with toxicity. The NTP conducts reproductive toxicity studies on many of the chemicals that are nominated for testing by the Program. This includes measures of effects on fertility and reproductive performance using a continuous breeding protocol. Other studies are conducted to determine the potential of agents to cause developmental toxicity following exposure of pregnant females. Studies are also done to evaluate the potential of chemicals to cause germ cell damage. Other systemic toxicities are tested, including potential effects on the function of the immune system and the nervous system. Toxicity to other organ systems is characterized, depending on the observations that are made in the subchronic toxicity studies. Carcinogenicity and chronic toxicity studies are conducted in rats and mice. As a sequel to this series of toxicological studies, additional studies of metabolism and pharmacokinetics are often conducted to help explain the nature of the toxicities that are observed, to better
Letters
79 (1995) 29-32
identify metabolites that might account for the toxicities, and to develop data to explain observed differences in gender responses, differences between the species or between routes of exposure. Other mechanistic studies are done to facilitate the final interpretation of the toxicological data. Examples of chemicals of major commercial importance that have been the subject of such toxicological investigation by the NTP include 1,3-butadiene, benzene, methylene chloride, and boric acid. Extensive studies of the metabolism and pharmacokinetics of butadiene were conducted to identify the metabolite which might account for the carcinogenic potential and to explain the significant difference in sensitivity between rats and mice. Extensive pharmacokinetic studies were conducted on benzene to better understand the metabolites which account for the observed carcinogenicity and to explain species differences in sensitivity. The NTP reported carcinogenic effects following inhalation of methylene chloride by mice. A significant increase in tumors of the lung and liver were reported. Studies were conducted to better understand the mechanisms by which methylene chloride caused these tumors in mice and to explain the importance of changes in cell replication as they might be causally related to the carcinogenic potential. Studies were also conducted to assess the two major metabolic profiles of methylene chloride and their relative contribution to the carcinogenicity. Boric acid has been confirmed as a reproductive and developmental toxicant in laboratory species by the NTP. A series of studies has been conducted to try to understand the mechanism by which boric acid might cause infertility in males, including investigations of target site dosimetry, genetic damage, and effects of cellular metabolism. In these and other cases, the NTP strives to characterize the toxicity of chemicals by integrating the knowledge from a range of studies. Data from specific responses are interpreted on the basis of the total body of data available. Two major workshops held during 1993 reinforced the importance of using bodies of knowledge to better predict toxicity. A workshop was held in March, 1993, to compare the predictiveness of carcino-
B.A. Schwerz 1 Toxicology Letters 79 (1995) 29-32
genicity induced b:y chemicals using systems developed by various investigators throughout the country. Predictions were sought regarding the outcome of more than 40 2-year carcinogenicity studies that were being conducted by the NTP. Upon the conclusion of the 2-year studies, this workshop was held to compare the predictiveness of the systems used by the various investigators. Such workshops help to identify shortcomings of predictive systems, and lead to refinements that will, hopefully, improve the predictiveness for carcinogenic potential. Another workshop held in November of 1993, sponsored by the United States Environmental Protection Agency (EPA), was held to evaluate the potential usefulness of benchmark doses as an approach for risk assessment of developmental toxicity studies and other manifestations of toxicity for which there are thresholds. A large portion of the data analyzed in this workshop was the results of NTP developmental toxicity studies. Workshops such as these are important steps in the process of improving the use of our toxicological data to predict potential hazards for human exposure. 2. Methods development The NTP has traditionally been a major contributor in the area of developing and refining toxicological test methods in all areas of toxicological testing. h4ajor contributions have been made in the area of genetic toxicity tests, carcinogenicity studies, reproductive and developmental toxicity studies, immunotoxicity, and neurotoxicity studies. Recently, a significant emphasis has been placed on t’he development of screens that use alternative systems and species, or in vitro systems. Efforts to develop alternative approaches are very important from the standpoint of developing better test methods, especially methods that minimize our dependence on the use of higher species of animals for toxicological testing. These systems, if effective, would also be more cost effective than extensive toxicological testing using large numbers of higher species. It is important to recognize, however, that approaches using in vitro systems or alternaitive species are a stop-gap measure to the goal for predicting toxicity and haz-
31
ard. The development of alternative approaches is a reasonable step to decrease our dependence on whole animal testing, but it is not the eventual goal that we have as scientists for being able to predict toxicity. The ultimate goal of predictive systems would be the development of knowledge bases that would permit us to develop answers to questions on the basis of information in the knowledge base without having to conduct animal studies to generate information on a screening basis. Animal studies might be done to confirm predictions from the knowledge base, but the knowledge base itself would be the basis of the estimates of toxicity and hazard. Efforts to develop such knowledge bases have not been highly successful, although they are more successful in some manifestations of toxicity than others. Knowledge bases, as opposed to databases, do not exist for most manifestations of toxicity today because we do not have enough information to build the knowledge bases. We continue to test chemicals singly or within structural families, but the knowledge is not adequate to be able to predict the toxicity of chemicals that are outside of a few chemical or pharmacological families. The process of generating information that has characterized our toxicology efforts over the last several decades is inefficient in producing knowledge bases that would preclude the need for additional routine testing. What we have learned from the random process of testing chemicals has reached an educational plateau and, while it meets the needs of having data on individual chemicals, large increments in knowledge do not happen from random testing of chemicals. In addition, support of basic biomedical research is also done on the basis of good science, a random process, rather than a well-defined strategy of research to develop certain knowledge to build knowledge bases. As a result, we do not have knowledge bases consisting of toxicological and other biological and chemical data that permit us to predict the toxicity of chemicals or other substances in the environment. To develop knowledge bases, we must develop a strategy for collecting the priority data needed to build knowledge bases. This would most effectively be done for those endpoints of toxicity where we have extensive knowledge from
32
B.A. Schetr
/ Toxicology Letters 79 (1995) 29-32
prior testing and understanding about mechanisms of toxicity. With such knowledge bases in hand, animal studies might be limited to confirmation of those biological properties that are predicted from the computerized knowledge bases or from other non-laboratory systems. Metabolism and pharmacokinetic data would obviously be a very important
component of these knowledge bases. Approaches such as physiologically based pharmacokinetic modeling would be important for answering such questions as the extrapolation between species and across routes of exposure, and to provide a basis for predicting levels of exposure at which some hazard might exist.