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Incomplete or Insufficient Data Sets

The evaluative process described in Chapter 2 and Chapter 3 and illustrated in Appendix A for 1,1,1,2-tetrafluoroethane (HFC-134a) and jet fuel JP-8 permits classification of exposure to a substance with respect to its reproductive and developmental toxicity if sufficient scientific data are available. The database required in each instance to permit confident classification must adequately characterize the full range of reproductive and developmental toxicity in humans and evaluate the associated hazards. In addition, the actual range of conditions of exposure must be known in sufficient detail to determine whether the dose, duration, timing, route, and other characteristics of exposure pose a substantial reproductive risk. In practice, such a complete database is rarely available. As will be apparent in Appendix A, the databases for JP-8 and HFC-134a are sufficient only in some aspects. This chapter discusses a common-sense approach to minimizing the risk when there are insufficient data available regarding a particular exposure to permit confident determination of the associated reproductive and developmental toxicity. This is a further application of the approach explained in Chapter 2 and Chapter 3 for interpreting toxicity data. The rationale is to avoid circumstances that create a high degree of concern.

PRINCIPLES TO MINIMIZE RISK

The principles used to minimize risk are the same whether or not the risk can be fully characterized. The principles also are the same



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Page 81 4 Incomplete or Insufficient Data Sets The evaluative process described in Chapter 2 and Chapter 3 and illustrated in Appendix A for 1,1,1,2-tetrafluoroethane (HFC-134a) and jet fuel JP-8 permits classification of exposure to a substance with respect to its reproductive and developmental toxicity if sufficient scientific data are available. The database required in each instance to permit confident classification must adequately characterize the full range of reproductive and developmental toxicity in humans and evaluate the associated hazards. In addition, the actual range of conditions of exposure must be known in sufficient detail to determine whether the dose, duration, timing, route, and other characteristics of exposure pose a substantial reproductive risk. In practice, such a complete database is rarely available. As will be apparent in Appendix A, the databases for JP-8 and HFC-134a are sufficient only in some aspects. This chapter discusses a common-sense approach to minimizing the risk when there are insufficient data available regarding a particular exposure to permit confident determination of the associated reproductive and developmental toxicity. This is a further application of the approach explained in Chapter 2 and Chapter 3 for interpreting toxicity data. The rationale is to avoid circumstances that create a high degree of concern. PRINCIPLES TO MINIMIZE RISK The principles used to minimize risk are the same whether or not the risk can be fully characterized. The principles also are the same

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Page 82 whether the risk under consideration is one related to developmental toxicity, reproductive toxicity, or another type of toxicity (e.g., pulmonary, neurological, renal). The toxicity produced by a particular exposure depends on a variety of factors, including the following: The chemical and toxicological nature of the agent itself. The agent's physical properties (e.g., solubility, volatility). The conditions of exposure (e.g., dose, duration, frequency, timing, route). The use of safety measures that reduce actual exposure (e.g., gloves, masks, and ventilation). The agent's pharmacokinetics of absorption, metabolism, distribution, and excretion, all of which are subject to individual variability. The pharmacodynamics (target organ, site of action, receptor interactions) that determine the agent's mechanism of action. Concomitant exposures to other chemical or physical agents that affect the factors listed above or the agent's toxic activity. Biological characteristics of the exposed individual (e.g., pregnancy, age, nutritional status, genetic susceptibility). The only way to eliminate completely the possibility of toxic effects associated with exposure to an agent is to eliminate all exposures. When use of the agent is necessary, minimizing the exposure will minimize risk. The guidelines below are for exposures that have not been adequately characterized with respect to reproductive and developmental toxicity, but for which there may be other data on toxicity, as listed above. Use expert judgment to evaluate the available toxicity data. Assume that susceptibility to reproductive or developmental toxicity may be greater than susceptibility to any known toxicity of the agent, and apply additional uncertainty factors to reflect the lack of data. Substitute exposure to an agent that is known not to be associated with substantial risk for causing reproductive and developmental toxicity for an agent associated with unknown risk.

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Page 83 If use of a given agent is unavoidable, the risk should be minimized by limiting the potentially absorbed dose. PRACTICAL APPLICATION When the reproductive and developmental risks of a particular exposure cannot be fully characterized, a conservative approach is to assume that such risks exist with exposure conditions below those that produce toxicity for the most sensitive system known for the agent. Toxicity to the “most sensitive system” is that produced by exposure to the agent at the lowest effective dose in any relevant species studied. The confidence with which one can apply this assumption to a particular exposure that has not been adequately studied depends on the amount of relevant information about the exposure in general. The less that is known, the greater the uncertainty, and the greater the degree of concern. This means there must be an inverse relationship between the quality of the information regarding reproductive and developmental toxicity and the size of the uncertainty factor required beyond the exposure limit, based on other kinds of toxicity. In general, however, the uncertainty factor should produce an exposure limit that is lower than that based on known toxicity of other kinds when the database for reproductive and developmental toxicity is inadequate. No chemical substance should be misused or abused. Whenever possible, an exposure that is known not to be associated with substantial reproductive or developmental toxicity should be substituted for an exposure associated with unknown risks. The decision to substitute one exposure for another or to eliminate a particular exposure altogether is always complicated. The factors to consider include physical and chemical characteristics such as molecular weight, volatility and vapor pressure, and the octanol-water partition coefficient (Kow). For example, if a chemical is a polymer with a molecular weight high enough that it is unlikely to be absorbed or distributed, it may be excluded from concern. Additional factors include other kinds of toxicity, ease and safety of storage, availability, and cost. Although reproductive and developmental toxicity can never be the only issues considered in such decisions, they must never be ignored. Reproductive and developmental toxicity are less likely to be associated with exposures that minimize absorption of the agent than

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Page 84 with greater exposures. Exposures associated with an unknown risk of reproductive and developmental toxicity should be as brief and as infrequent as possible. The amount of the agent used should be restricted and the method of use should be designed to reduce possible absorption. In addition, reasonable safety procedures and engineering safeguards should limit the exposure. Volatile materials should be used with adequate ventilation, if possible, and with appropriate masks or respirators when adequate ventilation is not possible. Proper gloves and protective garments should be used when handling materials that might be absorbed through the skin. Appropriate washing procedures should be used, and eating, drinking, and smoking should be prohibited in circumstances that might permit inadvertent ingestion of the agent. REDUCING UNCERTAINTY The approach described in this chapter results in limitations that would be unnecessary if the exposure under consideration were known to be safe. The most effective way to reduce uncertainty is to develop data to characterize the toxicity of the agents the Navy must use. Applying additional uncertainty factors to exposure limits can lead to unnecessarily conservative limits, which can lead the Navy to curtail the use of agents that may have been acceptable if adequate data were available. Such circumstances may increase costs. Obtaining a sufficient data set on the safety of a particular exposure might, therefore, provide substantial savings without increasing the risk of reproductive or developmental toxicity. Application of this approach will highlight those substances for which obtaining a more complete data set is a high priority. The Subcommittee on Reproductive and Developmental Toxicology recommends that the Navy commission or undertake the studies necessary to obtain additional information on agents in use or intended for use for which there is little or no information as an important means of reducing both uncertainty and expense. The subcommittee also recommends developing improved exposure assessments unique to the Navy environment and pertinent to exposures that are particularly important to assessing reproductive and

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Page 85 developmental toxicity. Those include exposures to males and females alike in various occupational situations and accounting for such factors as body size, the differences in the nature of the work and the workplace, and other factors that affect exposure, as well as the potential for contamination of the home environment secondary to workplace exposures.