The Office of Pollution Prevention and Toxics' Proposed Test Battery for the Children's Health Testing Program
On Earth Day 1998, Vice President Gore announced the Chemical Right-to-Know Initiative aimed at strengthening the public's right and ability to know about possible health and environmental hazards posed by exposure to industrial chemicals. The Chemical Right-to-Know Initiative includes the following three components: 1) obtaining screening level information for the high production volume chemicals, 2) lowering reporting thresholds for, and adding new persistent bioaccumulative toxic chemicals to EPA's Toxic Release Inventory, and 3) reviewing and reporting on what new testing may be needed to assess the special impact industrial chemicals may have on children.
In response to the Vice President, the Office of Pollution Prevention and Toxics (OPPT) is implementing the Chemical Right-to-Know Program. One aspect of this program is the Children's Health Testing Program which will be implemented using the authority of the Toxic Substances Control Act (TSCA). In initiating this testing program, decisions need to be made regarding the appropriate chemicals to test and the appropriate toxicology studies to conduct. The purpose of this report is to summarize OPPT's proposal for the toxicology studies to be included in the Children's Health Testing Program and to obtain scientific review by the SAP/SAB on this specific aspect of the Children's Health Testing Program.
OPPT has considered the recommendations outlined in the report of the Toxicology Working Group of the 10X Task Force. OPPT recognizes that the core toxicology data set that the Toxicology Working Group recommended was designed for conventional food use pesticides. However, OPPT in its implementation of the Children's Health Testing Program, plans to focus on chemicals to which children may have high potential exposure. The exposure characteristics of such chemicals might include those with high releases to the environment and/or high exposure due to their presence in consumer products. Due to the potential for high potential exposure, many of the same considerations made for conventional food use pesticides may apply for this program. The test battery that is being considered and the rationale are presented below.
In considering the appropriate toxicology studies for inclusion in the Children's Health Testing Program, OPPT is relying on the definition of developmental toxicity published in the EPA's Guidelines for Developmental Toxicity Risk Assessment and the additional explanations provided in the report of the Toxicology Working Group. Although the term "developmental toxicity" was used at the time the Agency published the risk assessment guidelines, it is considered to be the same as "toxicity to children" and the two terms are used interchangeably here. Developmental toxicity or "children's toxicity" is defined as adverse effects on the developing organism that may result from exposure prior to conception (to either parent), during prenatal development, or postnatally to the time of sexual maturation. It is important to recognize that many systems, particularly the skeletal and reproductive systems, do not become fully mature until young adulthood at 18-21 years of age. Thus, the exposure period of interest for assessing the potential toxicity of a chemical to children extends from prior to conception to sexual maturation which is completed around 18-21 years of age.
Adverse effects resulting from chemical exposure during development may be detected at any point in the life span of the organism. The major manifestations of developmental toxicity include: 1) death of the developing organism (e.g., spontaneous abortion, stillbirth, sudden infant death syndrome, or any shortening of the lifespan as a result of developmental exposures), 2) structural abnormalities (e.g. birth defects), 3) altered growth (e.g., growth retardation either prenatally or postnatally, including delayed or impaired development of secondary sexual characteristics during adolescence), and 4) functional deficits (e.g., mental retardation, learning deficits, respiratory disease including asthma, immune dysfunction, infertility or other reproductive impairments). Cancer as a result of developmental exposures is also considered part of developmental toxicity.
As discussed in the report of the Toxicology Working Group, the nature of the toxicity to the developing child will vary depending on the timing of exposure relative to the underlying developmental processes that are occurring. This can result in effects that are qualitatively very different in children and adults, or alternatively in effects that are qualitatively similar. For example, if exposure occurs prior to conception, during early embryonic development and/or critical stages of organogenesis, the nature and consequences of the outcomes are very different from the outcomes experienced by an adult exposed to the same chemical. This difference is due to the fact that the systems in the adult are mature and are no longer subject to the same kinds of perturbations as in the early stages of development. If exposure occurs later in development, such that the organ systems are functional but not fully mature, the toxicity observed in the child may be similar in nature to that observed in an adult. However, the degree of response in the child may differ from the adult due to a variety of factors, including more rapid cell turnover or incomplete maturation of enzyme systems for activation or detoxification of potentially toxic chemicals. Thus, the effects on the child may be qualitatively the same as those in the adult, but may occur at a different dose level, may show a different latency period, and/or the long term consequences may be different. It is also important to recognize that since organ systems become fully mature at different ages, some organ systems in the child, especially during adolescence, may respond similarly as in the adult.
The Toxicology Working Group recommended a core toxicology data set for the assessment of the potential toxicity of conventional food use pesticides on children's health. In addition, a number of additional toxicology studies are discussed in the report that may be triggered on the basis of the results obtained from the core set. These conditional studies would then become part of the core data set for a specific pesticide. The conditional studies include studies for which test guidelines exist, as well as studies which require the development of new test guidelines. In considering the test battery for the Children's Health Testing Program, OPPT restricted the studies to those that are included in the core toxicology data set. If the results from these studies indicate a concern and the need for further testing of a specific chemical, OPPT will consider these needs in a future proceeding.
The core toxicology data set recommended in the report of the Toxicology Working Group for conventional food use pesticides is intended to characterize toxicity after exposure for various lengths of time and by different routes of exposure depending on the route of concern. It includes toxicology studies that analyze the various organ systems in adults and developing organisms. Analysis of adults and developing organisms is important for several reasons. As stated above, the response of a child to chemical exposure will vary depending on the timing of exposure. In some cases, the outcome may be qualitatively very different from an adult. In other cases, the outcome may be qualitatively similar to that experienced by an adult although quantitatively the two may differ. Thus, adult data may provide information on target organs to evaluate in the reproduction studies or other developmental studies. In addition, adult studies provide information on target organs that may also be affected in children who are at an age where the organ systems have formed but are functionally less mature than adults. Finally, since some organ systems are fully mature at different ages and children include adolescents up to 18-21 years of age, adult data will provide relevant information about potential target organs during this later period of development as well.
OPPT relied on the above considerations in determining the studies to be included in the children's test battery. OPPT is proposing a test battery for the Children's Health Testing Program that is very similar to the core toxicology data set recommended by the Toxicology Working Group for conventional food use pesticides. This battery is also similar to the test battery which was proposed for use in the inhalation testing of 23 Hazardous Air Pollutants (HAPs) characterized by high air releases (61 FR 33178, as amended 62 FR 67466). The proposed Children's Health Testing Program battery includes the following studies which would be conducted by the route(s) most relevant for human exposure where applicable:
In vitro and in vivo mutagenicity studies
Metabolism study in rodents
Acute toxicity study
Subchronic (90-day) toxicity studies in two species (mice and rats)
Prenatal developmental toxicity studies in rodents and nonrodents (rats and rabbits preferred)
Two-generation reproduction study in rodents (usually rats)
Developmental neurotoxicity study in rodents (usually rats)
Neurotoxicity screening battery in rodents (usually rats)
Immunotoxicity study in rodents
Carcinogenicity or combined chronic and carcinogenicity studies in two species (mice and rats)
The proposed test battery differs from that recommended for conventional food use pesticides in two areas. First, it does not include subchronic or chronic studies in nonrodents. OPPT beleives that the rodent studies are adequate to characterize the potential hazard of the chemicals and OPPT is not proposing to include nonrodent subchronic or chronic studies at this time. OPPT will evaluate the need and/or anticipated added benefit of the nonrodent studies on a case by case basis pending the results of the other studies. Second, the proposed test battery does not include the acute eye and dermal irritation studies or dermal sensitization studies. These are not included since the most relevant routes of exposure are likely to be oral and inhalation, and therefore are not likely to provide useful information at this time. If this information becomes relevant for specific chemicals, OPPT will evaluate the need for the studies in the future. The Children's Health Testing Program battery differs from the testing battery in the proposed HAPs test rule in that it adds developmental neurotoxicity and includes carcinogenicity testing as a required study rather than as a triggered study based on the results of the mutagenicity and subchronic studies.
In the past, OPPT has considered some of the studies in the proposed Children's Health Testing Program battery to be "Tier 2" studies and they were triggered based on the results of other studies. However, the issue of triggering with reference to the developmental neurotoxicity study was considered by the Toxicology Working Group and their analysis suggests that triggers may not be inclusive enough to target appropriate studies for all chemicals. OPPT will be recommending that the studies be conducted in a logical order. For example, the development of the metabolism/pharmacokinetic data will be encouraged early in the process to aid in the appropriate design of the toxicology studies. The conduct of the subchronic studies will be encouraged prior to the conduct of the two-generation reproduction study to provide information of potential target organs. In addition, OPPT will be encouraging that studies be combined whenever possible. For example, the immunotoxicity study and neurotoxicity screening battery can be combined with the subchronic study, and the developmental neurotoxicity study can be combined with the prenatal developmental toxicity study or the two-generation toxicity study.
- Is the proposed Children's Health Testing Program battery appropriate to evaluate the potential hazards of industrial/commercial chemicals to which children may have high potential exposure? If not, what modifications are recommended?
- Does the SAP/SAB agree that the proposed battery should be viewed as a single tier of studies? If not, what studies in the proposed test battery are recommended as tier 2 studies and what triggers could be used to move from tier 1 to tier 2?
- Does the SAP/SAB have any recommendations as to the order of conduct of studies in the Children's Health Testing Program?