Exposure-response doses

Keywords Aerosol number and size distributions, Engineered nanoparticles, European environment, Exposure-response doses, Ultrafine particles... 

Inhalation dosimetry plays a vital role in determining the links between exposure and human health effects. In the following paragraph, preliminary estimates of respiratory deposition doses are made for indicating exposure-response-doses at various European locations. These estimates are made based on the observed... 

Some biomarker responses provide evidence only of exposure and do not give any reliable measure of toxic effect. Other biomarkers, however, provide a measure of toxic effects, and these will be referred to as mechanistic biomarkers. Ideally, biomarker assays of this latter type monitor the primary interaction between a chemical and its site of action. However, other biomarkers operating down stream from the original toxic lesion also provide a measure of toxic action (see Figure 14.3 in Chapter 14), as, for instance, in the case of changes in the transmission of action potential... 

No information is available concerning the effects of 2,3-benzofuran in humans. Acute oral exposure to 2,3-benzofuran has been shown to alter levels of enzyme activity in the livers of female mice (Heine et al. 1986), but much more work would need to be done to determine whether there is a pattern of enzyme alteration specific to 2,3-benzofuran exposure. Other effects found in animals following oral exposure to 2,3-benzofuran are kidney and liver damage and kidney, lung, liver, and stomach cancer (see Section 2.2.2). Such generalized responses do not suggest the basis for any specific biomarker of clinical or preclinical effects caused by 2,3-benzofuran. 

Studies of working women present the potential for additional bias, because some factors that influence employment status may also affect reproductive end-points. For example, because of child care responsibilities, women may terminate employment, as might women with a history of reproductive problems who wish to have children and are concerned about workplace exposures (Joffe, 1983 Lemasters Pinney, 1989). Thus, retrospective studies of female exposure that do not include terminated female workers may be of limited use in risk assessment, because the level of risk for some of the outcomes is likely to be overestimated (Lemasters Pinney, 1989). 

This chapter has described the pharmacokinetics of PT 2 -MOE partially modified ASO following parenteral administration, and has shown that ASOs in this chemical class distribute extensively to many tissue types, with prolonged half-lives. Moreover, exposure-response relationships have been established in both animal models and humans. However, there are a few tissues to which parenter-ally administered oligonucleotides do not distribute, or are distributed minimally these include brain, muscle, eyes, and skin. Consequently, ASOs targeted to these tissues will require local delivery, as outlined in Chapter 10. 

Second, there are biometrical requirements. Various exposure response models may be used and compared. The models need to be clearly defined, and goodness of fit should be reported, both for the separate exposures as well as for the mixtures. Concentration addition, response addition, and mixed-model results may be compared as possible alternatives, especially when underpinning of mechanistic assumptions is weak. Results at one exposure level (e.g., EC50) do not necessarily predict results at other exposure levels due to different slopes and positions of the curves for separate compounds and the mixtures. Statistical tests should be executed properly to compare predicted and observed responses. If any statements about the significance of results are made, the methods of dose-response analysis need to be reported. 

The Thacker et al. (1992) conclusions did not factor in the role of exposure profile and Pb toxicokinetic differences in affecting the form of the most significant results within and across studies. Mushak (1993) analyzed differences across the early results in phases of the prospective studies and demonstrated that the toxicokinetic and exposure differences do in fact account for dose—response differences. 

It is important to note that these exposure levels do not equal doses, which govern the toxic responses from chemical exposure. It is not until the chemicals are actually absorbed into the body that someone receives a chemical dose. This concept is more fully discussed in chapter 6. 

Some sites are easy to elassify due to their inehision on the National Priorities List (NPL), state superfund, or other regulatory list. In other eases, debate ean and does arise to determine if a site should be treated as hazardous. Eor example, some sites eommonly referred to as brown fields have eontamination levels that are eonsidered low. Sometimes levels of eontamination are so low that exposure levels to workers do not reaeh aetion levels or permissible exposure levels (PEL). Some firms have ehosen to treat low-level eontaminated sites as if they fell under HAZWOPER requirements. This is a somewhat eonservative approaeh whieh provides a eomfort faetor for management and potentially responsible parties (PRP) or other entities. 

Altliough the technical conununity has come a long way in understanding how to do a better job in luizard identification, dose-response assessment, and exposure assessment portions of risk assessment, it lias only begun to understand how to best cluiractcrize hcaltli risks and how to present tliese risks most appropriately to both the public and decision makers. Tlie next tliree sections specifically address tlicse issues. Tliis section deals witli qualitative risk assessment while tlie next two sections deal witli quantitative risk assessment. 

If the exposure level (E) exceeds tliis tlireshold (i.e., E/RfD exceeds unity), tliere may be concern for potential noncancer effects. As a rule, tlie greater tlie value of E/RfD above unity, tlie greater tlie level of concern. However, one should not interpret ratios of E/RfD as statistical probabilities a ratio of 0.001 does not mean tliat tliere is a one in one tliousand cliance of the effect occurring. Furtlier, it is important to empliasize tliat tlie level of concern does not increase linearly as tlie RfD is approached or exceeded because RfDs do not have equal accuracy or precision and are not based on tlie same severity of toxic effects. Thus, tlie slopes of the dose-response curv e in excess of the RfD can range widely depending on tlie substance. 

Immunotoxicity. Limited information is available regarding the effects of endosulfan on the human immune system. However, specially designed studies using rats indicate that both humoral and cellular immune responses are depressed by ingested endosulfan at doses that do not induce any overt signs of toxicity (Banerjee and Hussain 1986,1987). In vitro studies support the possibility that endosulfan affects immune system function (Das et al. 1988). These results demonstrate that immunotoxicity may be a more sensitive end point of endosulfan-induced toxicity than other end points, and humans may be at risk for adverse immune effects following exposure to endosulfan. An intermediate-duration oral MRL was derived based on the observation of depressed immune responses (Banerjee and Hussain 1987). 

Animal studies have shown that tumors can result from both inhalation (Fukuda et al. 1983 Henschler et al. 1980 Maltoni et al. 1986) and oral exposure (Aima et al. 1994 Henschler et al. 1984 NCI 1976 NTP 1990) to trichloroethylene. Unfortunately, some of these studies (NCI 1976) are limited in that they use carcinogenic epoxide stabilizers with the trichloroethylene, which may contribute to the carcinogenicity. The studies also show different responses depending on the sex, species, and strains of animals used and do not point to a particular target organ for increased tumor incidence. Other studies are flawed because of excess... 

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