ReproductiveToxicology,Vol. 6, pp. 99-108, 1992
0890-6238/92$5.00 + .00 Copyright© 1992PergamonPressplc
Printed in the U.S.A.All rightsreserved.
• Special Article
PRIORITIZING CANDIDATE REPRODUCTIVE/DEVELOPMENTAL TOXICANTS FOR EVALUATION JAMES M . D O N A L D , LAURIE E. M O N S E R R A T , K I M H O O P E R , STEVEN A.
BOOK, and GERALD F. CHERNOFF
California Department of Health Services, Health Hazard Assessment Division, Reproductive and Cancer Hazard Assessment Section, Sacramento and Berkeley (KH), California Abstract -- To provide a rational method for the timely evaluation of possible reproductive/developmental toxicants, a prioritization scheme was developed by the California Department of Health Services to select chemicals for consideration by the Proposition 65 Scientific Advisory Panel. Initially, four ascertainment methods were used to identify and construct a master list of 164 candidate agents. Using two criteria, the potential for human exposure and the perceived reproductive/developmental hazard as judged by an ad hoc committee of experts, 42 candidates from the master list were identified as priority agents. For practical purposes, the 15 priority agents with the highest rankings will be given the highest priority in the review process. Limitations in the prioritization method used and refinements to be incorporated in an annual update are described. Key Words: Proposition 65; reproductive/developmental toxicants; teratogens; prioritizing; evaluation; priority lists.
and developmental data on candidate agents, and making recommendations to the Panel for subsequent addition of agents to the list of chemicals known to the State to cause developmental or reproductive toxicity. This method, shown in Figure 1, represents one of several methods by which chemicals may be added to the Governor's list. Other methods, not addressed in this paper, include the listing of agents identified as RDTs by bodies recognized as "authoritative" for the purposes of Proposition 65, and those agents formally identified by a State or federal agency as causing reproductive/developmental toxicity. Initially, chemicals were recommended for listing based on their well-recognized ability to disrupt development or reproduction in the human population. In some later cases, agents were listed by administrative mechanisms as RDTs based on the labeling or identification requirements of the US Food and Drug Administration (3), and by the determinations of the US Environmental Protection Agency through the "authoritative bodies" approach (4). While these methods of selection were appropriate for those chemicals with clear-cut reproductive or developmental toxicity, they are limited in application for screening the large number of agents to which the population is exposed (5-7). For example, in one well-respected review of over 2820 agents, 180 (6%) were shown to be clearly teratogenic
INTRODUCTION
In 1986, the voters of California approved the ballot initiative Proposition 65, the Safe Drinking Water and Toxic Enforcement Act of 1986 (1,2). One portion of the act requires that the "Governor shall cause to be published a list of those chemicals known to the State to cause . . . reproductive toxicity . . . and . . . shall cause such list to be revised and republished in light of additional knowledge at least once per year thereafter." To advise and assist the Governor in implementing this requirement, a Scientific Advisory Panel which functions as the Act's "state's qualified experts" was created by the lead agency, the California Health and Welfare Agency. The Reproductive and Cancer Hazard Assessment Section (RCHAS) within the Department of Health Services, a department of the Health and Welfare Agency, was charged with providing support to the Agency and to the Panel. This support includes the identification of candidate agents for consideration as possible reproductive and/or developmental toxicants (RDTs), evaluating the available scientific reproductive
Address correspondence to Gerald F. Chemoff, Office of Environmental Health Hazard Assessment, RCHAS, Room 476, 714 P Street, Sacramento, CA 95814. 99
100
Reproductive Toxicology
Volume6, Number 1, 1992
Identification of Candidate Agents and Construction of a Master List
rather than an individual agent, or if they had already been listed as RDTs under Proposition 65. The 77 agents identified by this method are shown on the master list in Appendix 1, under ascertainment by method L.
Prioritization of Candidate Agents
2. Identification by experts
Evaluation of High Priority Candidates
Recommendation for F u r t h e r Action Fig. 1. An overview of the prioritization process.
in two or more species of test animals, 602 (21%) were considered probably teratogenic, and 291 (10%) were judged to be possibly teratogenic (8). Given the magnitude of these numbers, which do not include male or female reproductive toxicants or other nonteratogenic developmental toxicants, it is clear that alternative methods of identifying and prioritizing candidate agents for consideration as RDTs are required. To our knowledge, there are no generally accepted methods for such a prioritization. The purpose of this report is to describe the method developed and currently used by the RCHAS staff in selecting agents to be evaluated for reproductive and developmental toxicity for subsequent consideration by the Panel. This method evolved, in part, from an earlier pilot study that indexed potential RDTs by surrogate exposure data (9). C O N S T R U C T I O N OF THE M A S T E R LIST As shown in Figure 1, the first step in the listing process is to construct a master list or pool of candidate agents for which there is believed to be evidence for potential reproductive and or developmental toxicity. Since the goal of this step is to be as comprehensive as possible, four methods of ascertainment were used.
More than 200 recognized experts in the fields of andrology, behavioral teratology, clinical obstetrics, developmental biology, epidemiology, gynecology, industrial hygiene, neurobehavioral toxicology, occupational medicine, pediatric dysmorphology, public health, reproductive biology, teratology, toxicology, and members of the public health community were asked to submit the names of agents that they believed should be given a high priority for consideration for listing under Proposition 65. In addition, members of the Reproductive Toxicity Subpanel of the Panel submitted a list of agents that they desired to have considered as candidates. Agents that represented a group or class of chemicals or which had already been listed under Proposition 65, were excluded. The 130 agents identified by this method are shown on the master list under ascertainment by method E.
3. Identification by agencies The findings of scientific bodies and/or regulatory agencies who in some way identify agents as RDTs or who set standards based on reproduction and developmental endpoints, were reviewed. These agencies, which do not include groups identified as "authoritative bodies" for purposes of the act (4), include the Hazard Evaluation System and Information Service of the California Department of Health Services, the State of California Air Resources Board, the California Occupational Safety and Health Administration, the California Department of Food and Agriculture, the State Water Resources Control Board, the American Conference of Government Industrial Hygienists, and the federal Occupational Safety and Health Administration. After eliminating those agents that represented a group or class of chemicals or that had already been listed as RDTs under Proposition 65, 25 were identified and are shown on the master list under ascertainment by method A.
1. Identification from published literature Lists of candidate agents from the published literature were reviewed (8,10-27). Two lists were judged to be reliable and presented in a format amenable for use in identifying candidates for the master list (8,10). Agents were excluded if there were no human data, if teratogenicity had been demonstrated in only one species, if they represented a group or class of chemicals
4. Identification by the Modified Hazardous Air Pollutant Prioritization System (MHAPPS ) The MHAPPS system contains mutagenicity, reproductive, and developmental toxicity information on approximately 1000 agents abstracted from the Registry of Toxic Effects of Chemical Substances (RTECS). Numerical values given to an agent are based on the
Prioritizing candidate RDTs • J. M. DONALDET AL. amount of information available. Scores for reproductive and developmental toxicity range between 5 (effects demonstrated in only one species) and 21 (effects demonstrated in humans and 2 animal species), while mutagenicity scores range from 0.8 (scheduled for mutagenicity testing) to 4.9 (in vivo mammalian mutagen). Using this approach, each chemical was scored for its mutagenic, reproductive and developmental toxic potential. After removing agents that represented a group or class of chemicals or that were already listed under Proposition 65, chemicals with scores greater than 11 were identified and appear on the master list under ascertainment by method M. Utilizing these four methods of ascertainment, a master list was complied that contained the 164 candidate agents presented in Appendix 1. It must be emphasized that inclusion in the master list of candidate agents does not identify an agent as a RDT. Only after a thorough and complete evaluation of the relevant scientific literature has been conducted can a candidate agent be recommended for consideration for listing. P R I O R I T I Z A T I O N OF AGENTS Once the master list of candidate agents was constructed, the next task was to prioritize the agents for future evaluation (Figure 1). One means by which agents can be prioritized is by the likelihood of a significant human exposure. In this scheme, agents with the greatest potential for exposure would be given the highest ranking in the prioritization process. Unfortunately, sources of data on actual human exposures to the candidate agents on the master list are lacking, and surrogate data based on production, usage, and emissions, have been used as the best available substitute (see Appendix 1). Given this limitation, surrogate exposure data were collected from six different sources:
1. SARA313 The Toxic Chemical Release Inventory developed under Superfund Amendments and Reauthorization ACT (SARA) contains information on releases of selected chemicals from manufacturing facilities to the air, surface waters, underground injections, and landfills (9,28). Data were available for 26 of the candidate agents on the master list. 2. CALPEST The California Pesticide Use Report (CALPEST) summarizes pesticide usage in California by structural and agricultural pest control operators; information from State, Federal, and local agencies; and information from growers applying restricted materials (9,29). Data were available for 22 candidate agents on the master list.
101
3. TSCA The Toxic Substances Control Act (TSCA) contains production information on more than 68,000 chemicals used in US commerce (9,30). Data were available for 7 candidate agents on the master list. 4. CARB The California Air Resources Board reports ambient toxic air contaminants in air emissions (31). Preliminary data were available for 9 candidate agents on the master list. 5. US Production US production of selected agents was obtained from a publication in the open literature (32). Data were available for 12 of the candidate agents on the master list. 6. Occupational Exposure Limits The US Occupational Safety and Health Administration sets "permissible exposure limits" (PELs) for agents that are, or were, considered a potential hazard in the workplace (33). PELs or similar occupational standards were available for 58 candidate agents on the master list. Using these 6 sources, exposure data were obtained for 67 agents on the master list. These data are given in columns C through H of the master list in Appendix 1. In addition to ranking by potential for human exposure, agents can be ranked on the basis of their perceived hazard as determined by experts in the field and/or the general public. One method for gathering this information is to use an "experts" approach. For this purpose, an ad hoc committee of 42 experts was established from the list of experts who responded to the initial request for nominations in the identification phase described earlier. Each committee member was sent the master list and asked to select the top 20 agents they perceived as posing the greatest reproductive or developmental hazard to the human population. They were requested to rank the agents from 1 to 20 (highest to lowest) with respect to the sequence in which they should be considered. Of the 13 committee members responding to the request, 4 ranked the agents as requested, and the remaining 9 listed agents of concern without giving them a ranking. Taken together, the committee members selected a total of 74 separate agents. Since only 4 members ranked the agents as requested, an alternative method of ranking the collected data was employed. In this scheme, each agent selected for priority consideration by a committee member was given a numerical score of 10. The total score for each
Reproductive Toxicology
102
Volume 6, Number 1, 1992
Table 1. Priority list of candidate agents (Inclusion o f an agent on this list does not identify it as an R D T )
Class Rank 1 2 3 3 4 4 4 4 4 4 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7
Chemical Name
arsenic (inorganic) cadmium formaldehyde vinyl chloride aldrin carbon tetrachloride chlordane DDT ethylene dibromide methylene chloride trichloroethylene acrylamide benzene butadiene, 1,3ethylene thiourea benzo-a-pyrene beryllium chromium chromium trioxide copper sulfate dichloroethylene, 1,1hexane, nmethoxyethyl acetate, 2nickel carbonyl phenol toluene, 2,4-diisocyanate xylene boric acid butyl ester, 2,4-D carbon dioxide chloroform dichloropropane, 1,2endrin epichlorohydrin ethoxyethyl acetate, 2folpet formamide halothane heptachlor manganese methyl butyl ketone toxaphene
CAS # 7440382 7440439 50000 75014 309002 56235 57749 50293 106934 75092 79016 79061 71432 106990 96457 50328 7440417 18540299 1333820 7758987 75354 110543 110496 13463393 108952 584849 1330207 10043353 94804 124389 67663 78875 72208 106898 111159 133073 75127 151677 76448 7439965 591786 8001352
SARA313 Emissions (lbs)
Pesticides Usage (lbs)
17194 2490 448941 1041 35849
1605 5671865 117327 3988 430895 5989 250
2
TSCA Production (lbs)
ARB Emissions (ppb) a
US Occupational Prod. Exposure million lbs Standards
1.65E+08 7.48E+07 3.08E+08
85
6369 9617
143 2622 16316
0890-6238/92$5.00 + .00 Copyright© 1992PergamonPressplc
Printed in the U.S.A.All rightsreserved.
• Special Article
PRIORITIZING CANDIDATE REPRODUCTIVE/DEVELOPMENTAL TOXICANTS FOR EVALUATION JAMES M . D O N A L D , LAURIE E. M O N S E R R A T , K I M H O O P E R , STEVEN A.
BOOK, and GERALD F. CHERNOFF
California Department of Health Services, Health Hazard Assessment Division, Reproductive and Cancer Hazard Assessment Section, Sacramento and Berkeley (KH), California Abstract -- To provide a rational method for the timely evaluation of possible reproductive/developmental toxicants, a prioritization scheme was developed by the California Department of Health Services to select chemicals for consideration by the Proposition 65 Scientific Advisory Panel. Initially, four ascertainment methods were used to identify and construct a master list of 164 candidate agents. Using two criteria, the potential for human exposure and the perceived reproductive/developmental hazard as judged by an ad hoc committee of experts, 42 candidates from the master list were identified as priority agents. For practical purposes, the 15 priority agents with the highest rankings will be given the highest priority in the review process. Limitations in the prioritization method used and refinements to be incorporated in an annual update are described. Key Words: Proposition 65; reproductive/developmental toxicants; teratogens; prioritizing; evaluation; priority lists.
and developmental data on candidate agents, and making recommendations to the Panel for subsequent addition of agents to the list of chemicals known to the State to cause developmental or reproductive toxicity. This method, shown in Figure 1, represents one of several methods by which chemicals may be added to the Governor's list. Other methods, not addressed in this paper, include the listing of agents identified as RDTs by bodies recognized as "authoritative" for the purposes of Proposition 65, and those agents formally identified by a State or federal agency as causing reproductive/developmental toxicity. Initially, chemicals were recommended for listing based on their well-recognized ability to disrupt development or reproduction in the human population. In some later cases, agents were listed by administrative mechanisms as RDTs based on the labeling or identification requirements of the US Food and Drug Administration (3), and by the determinations of the US Environmental Protection Agency through the "authoritative bodies" approach (4). While these methods of selection were appropriate for those chemicals with clear-cut reproductive or developmental toxicity, they are limited in application for screening the large number of agents to which the population is exposed (5-7). For example, in one well-respected review of over 2820 agents, 180 (6%) were shown to be clearly teratogenic
INTRODUCTION
In 1986, the voters of California approved the ballot initiative Proposition 65, the Safe Drinking Water and Toxic Enforcement Act of 1986 (1,2). One portion of the act requires that the "Governor shall cause to be published a list of those chemicals known to the State to cause . . . reproductive toxicity . . . and . . . shall cause such list to be revised and republished in light of additional knowledge at least once per year thereafter." To advise and assist the Governor in implementing this requirement, a Scientific Advisory Panel which functions as the Act's "state's qualified experts" was created by the lead agency, the California Health and Welfare Agency. The Reproductive and Cancer Hazard Assessment Section (RCHAS) within the Department of Health Services, a department of the Health and Welfare Agency, was charged with providing support to the Agency and to the Panel. This support includes the identification of candidate agents for consideration as possible reproductive and/or developmental toxicants (RDTs), evaluating the available scientific reproductive
Address correspondence to Gerald F. Chemoff, Office of Environmental Health Hazard Assessment, RCHAS, Room 476, 714 P Street, Sacramento, CA 95814. 99
100
Reproductive Toxicology
Volume6, Number 1, 1992
Identification of Candidate Agents and Construction of a Master List
rather than an individual agent, or if they had already been listed as RDTs under Proposition 65. The 77 agents identified by this method are shown on the master list in Appendix 1, under ascertainment by method L.
Prioritization of Candidate Agents
2. Identification by experts
Evaluation of High Priority Candidates
Recommendation for F u r t h e r Action Fig. 1. An overview of the prioritization process.
in two or more species of test animals, 602 (21%) were considered probably teratogenic, and 291 (10%) were judged to be possibly teratogenic (8). Given the magnitude of these numbers, which do not include male or female reproductive toxicants or other nonteratogenic developmental toxicants, it is clear that alternative methods of identifying and prioritizing candidate agents for consideration as RDTs are required. To our knowledge, there are no generally accepted methods for such a prioritization. The purpose of this report is to describe the method developed and currently used by the RCHAS staff in selecting agents to be evaluated for reproductive and developmental toxicity for subsequent consideration by the Panel. This method evolved, in part, from an earlier pilot study that indexed potential RDTs by surrogate exposure data (9). C O N S T R U C T I O N OF THE M A S T E R LIST As shown in Figure 1, the first step in the listing process is to construct a master list or pool of candidate agents for which there is believed to be evidence for potential reproductive and or developmental toxicity. Since the goal of this step is to be as comprehensive as possible, four methods of ascertainment were used.
More than 200 recognized experts in the fields of andrology, behavioral teratology, clinical obstetrics, developmental biology, epidemiology, gynecology, industrial hygiene, neurobehavioral toxicology, occupational medicine, pediatric dysmorphology, public health, reproductive biology, teratology, toxicology, and members of the public health community were asked to submit the names of agents that they believed should be given a high priority for consideration for listing under Proposition 65. In addition, members of the Reproductive Toxicity Subpanel of the Panel submitted a list of agents that they desired to have considered as candidates. Agents that represented a group or class of chemicals or which had already been listed under Proposition 65, were excluded. The 130 agents identified by this method are shown on the master list under ascertainment by method E.
3. Identification by agencies The findings of scientific bodies and/or regulatory agencies who in some way identify agents as RDTs or who set standards based on reproduction and developmental endpoints, were reviewed. These agencies, which do not include groups identified as "authoritative bodies" for purposes of the act (4), include the Hazard Evaluation System and Information Service of the California Department of Health Services, the State of California Air Resources Board, the California Occupational Safety and Health Administration, the California Department of Food and Agriculture, the State Water Resources Control Board, the American Conference of Government Industrial Hygienists, and the federal Occupational Safety and Health Administration. After eliminating those agents that represented a group or class of chemicals or that had already been listed as RDTs under Proposition 65, 25 were identified and are shown on the master list under ascertainment by method A.
1. Identification from published literature Lists of candidate agents from the published literature were reviewed (8,10-27). Two lists were judged to be reliable and presented in a format amenable for use in identifying candidates for the master list (8,10). Agents were excluded if there were no human data, if teratogenicity had been demonstrated in only one species, if they represented a group or class of chemicals
4. Identification by the Modified Hazardous Air Pollutant Prioritization System (MHAPPS ) The MHAPPS system contains mutagenicity, reproductive, and developmental toxicity information on approximately 1000 agents abstracted from the Registry of Toxic Effects of Chemical Substances (RTECS). Numerical values given to an agent are based on the
Prioritizing candidate RDTs • J. M. DONALDET AL. amount of information available. Scores for reproductive and developmental toxicity range between 5 (effects demonstrated in only one species) and 21 (effects demonstrated in humans and 2 animal species), while mutagenicity scores range from 0.8 (scheduled for mutagenicity testing) to 4.9 (in vivo mammalian mutagen). Using this approach, each chemical was scored for its mutagenic, reproductive and developmental toxic potential. After removing agents that represented a group or class of chemicals or that were already listed under Proposition 65, chemicals with scores greater than 11 were identified and appear on the master list under ascertainment by method M. Utilizing these four methods of ascertainment, a master list was complied that contained the 164 candidate agents presented in Appendix 1. It must be emphasized that inclusion in the master list of candidate agents does not identify an agent as a RDT. Only after a thorough and complete evaluation of the relevant scientific literature has been conducted can a candidate agent be recommended for consideration for listing. P R I O R I T I Z A T I O N OF AGENTS Once the master list of candidate agents was constructed, the next task was to prioritize the agents for future evaluation (Figure 1). One means by which agents can be prioritized is by the likelihood of a significant human exposure. In this scheme, agents with the greatest potential for exposure would be given the highest ranking in the prioritization process. Unfortunately, sources of data on actual human exposures to the candidate agents on the master list are lacking, and surrogate data based on production, usage, and emissions, have been used as the best available substitute (see Appendix 1). Given this limitation, surrogate exposure data were collected from six different sources:
1. SARA313 The Toxic Chemical Release Inventory developed under Superfund Amendments and Reauthorization ACT (SARA) contains information on releases of selected chemicals from manufacturing facilities to the air, surface waters, underground injections, and landfills (9,28). Data were available for 26 of the candidate agents on the master list. 2. CALPEST The California Pesticide Use Report (CALPEST) summarizes pesticide usage in California by structural and agricultural pest control operators; information from State, Federal, and local agencies; and information from growers applying restricted materials (9,29). Data were available for 22 candidate agents on the master list.
101
3. TSCA The Toxic Substances Control Act (TSCA) contains production information on more than 68,000 chemicals used in US commerce (9,30). Data were available for 7 candidate agents on the master list. 4. CARB The California Air Resources Board reports ambient toxic air contaminants in air emissions (31). Preliminary data were available for 9 candidate agents on the master list. 5. US Production US production of selected agents was obtained from a publication in the open literature (32). Data were available for 12 of the candidate agents on the master list. 6. Occupational Exposure Limits The US Occupational Safety and Health Administration sets "permissible exposure limits" (PELs) for agents that are, or were, considered a potential hazard in the workplace (33). PELs or similar occupational standards were available for 58 candidate agents on the master list. Using these 6 sources, exposure data were obtained for 67 agents on the master list. These data are given in columns C through H of the master list in Appendix 1. In addition to ranking by potential for human exposure, agents can be ranked on the basis of their perceived hazard as determined by experts in the field and/or the general public. One method for gathering this information is to use an "experts" approach. For this purpose, an ad hoc committee of 42 experts was established from the list of experts who responded to the initial request for nominations in the identification phase described earlier. Each committee member was sent the master list and asked to select the top 20 agents they perceived as posing the greatest reproductive or developmental hazard to the human population. They were requested to rank the agents from 1 to 20 (highest to lowest) with respect to the sequence in which they should be considered. Of the 13 committee members responding to the request, 4 ranked the agents as requested, and the remaining 9 listed agents of concern without giving them a ranking. Taken together, the committee members selected a total of 74 separate agents. Since only 4 members ranked the agents as requested, an alternative method of ranking the collected data was employed. In this scheme, each agent selected for priority consideration by a committee member was given a numerical score of 10. The total score for each
Reproductive Toxicology
102
Volume 6, Number 1, 1992
Table 1. Priority list of candidate agents (Inclusion o f an agent on this list does not identify it as an R D T )
Class Rank 1 2 3 3 4 4 4 4 4 4 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7
Chemical Name
arsenic (inorganic) cadmium formaldehyde vinyl chloride aldrin carbon tetrachloride chlordane DDT ethylene dibromide methylene chloride trichloroethylene acrylamide benzene butadiene, 1,3ethylene thiourea benzo-a-pyrene beryllium chromium chromium trioxide copper sulfate dichloroethylene, 1,1hexane, nmethoxyethyl acetate, 2nickel carbonyl phenol toluene, 2,4-diisocyanate xylene boric acid butyl ester, 2,4-D carbon dioxide chloroform dichloropropane, 1,2endrin epichlorohydrin ethoxyethyl acetate, 2folpet formamide halothane heptachlor manganese methyl butyl ketone toxaphene
CAS # 7440382 7440439 50000 75014 309002 56235 57749 50293 106934 75092 79016 79061 71432 106990 96457 50328 7440417 18540299 1333820 7758987 75354 110543 110496 13463393 108952 584849 1330207 10043353 94804 124389 67663 78875 72208 106898 111159 133073 75127 151677 76448 7439965 591786 8001352
SARA313 Emissions (lbs)
Pesticides Usage (lbs)
17194 2490 448941 1041 35849
1605 5671865 117327 3988 430895 5989 250
2
TSCA Production (lbs)
ARB Emissions (ppb) a
US Occupational Prod. Exposure million lbs Standards
1.65E+08 7.48E+07 3.08E+08
85
6369 9617
143 2622 16316
