(CASAC) Peer Review of EPA's Integrated Science Assessment

eorganized to focus on studies using more relevant concentrations of SO 2 andsections were added to better discuss mode of action and potential particle-SO 2interactions. We are requesting CASAC review specifically on these analyses aswell as on the integration of the overall evidence from the human clinical, animaltoxicological, and epidemiological studies.Chapter 3 is vastly improved from the previous draft of the ISA. The newanalyses of human clinical studies are helpful. CASAC believes, however, that moreemphasis should be placed on effects seen at concentrations lower than 0.4 ppm. ThePanel is concerned about the potential underestimation of the proportion of asthmaticpersons affected by short-term exposure to SO 2 because only mild and moderateasthmatic adults were recruited to participate in the clinical studies. People with moresevere asthma or poor control of their symptoms may be more susceptible and mayrespond more adversely to SO 2 and discussion of this point should be expanded in thechapter. The potential influence of medication use on asthmatic responses to SO 2 shouldalso be discussed. In general, the evidence from the animal toxicological, controlledhuman exposure, and epidemiological studies has been satisfactorily integrated.However, the gap between the greater level of SO 2 used in the clinical studies and therelatively lower ambient concentrations associated with respiratory morbidity in theepidemiological studies needs to be clearly acknowledged. The relevance of the higherdose animal studies also needs to better developed. The results of the studies involvingextremely high levels of metal oxide or carbon-SO 2 mixtures suggest that SO 2 effectsmay be potentiated by co-exposure to particles, but the relevance of these results toambient exposures is unclear. Section 3.1.5 should be greatly condensed to give a morefocused discussion of the mechanistic implications of the mixture studies withoutpresentation of experimental details. While the new summary sections are a welcomeaddition to the chapter, their quality is uneven. It would be helpful if these sections werewritten in a style that applied the causal inference approach outlined in Chapter 1 in aconsistent manner.Charge Question 4: The section on concentration-response relationships in Chapter4 was reorganized and revised to include analysis of individual-level data from thehuman clinical studies and some additional discussion of the difficulties ofdiscerning a threshold in population-level data. In addition, revisions were made tobetter characterize groups likely to be susceptible or vulnerable to SOx and thepotential size of the population at risk for SOx-related health effects. Finally,revisions were made to reduce redundancy with material presented in Chapter 3.Have the revisions made to Chapter 4 improved the characterization of the potentialpublic health impact of SOx exposure?Revisions to Chapter 4 have improved the characterization of potential healthimpacts of SOx exposure, but additional clarification, evaluation, and amplification isneeded. The Panel recommends that EPA revisit the definitions of susceptibility andvulnerability. The definition of susceptibility should consider the form of the doseresponserelationship and the magnitude of response at a given dose. Greater clarity andspecificity is needed in the definition of this concept if it is to be used without ambiguity.iv