Dose-response relationships spectrum

The available data for deriving dose-response relationships for 144Ce are relatively limited. A complicating feature is that the spectrum of diseases produced is dependent upon the form of the 144Ce entering the body and the resultant radiation dose. This is apparent from data in Table 23 in which several different and competing diseases were produced by inhaled 144CeCl3. Additional factors that confuse the interpretation of internal emitter dose-response studies in laboratory... 

Pentachlorophenol is an effective broad-spectrum biocide widely used as a wood preservative. Two-year carcinogenicity studies had been conducted in B6C3F1 mice and similar studies were planned in Fischer 344 rats. To aid in future comparison of the results of the toxicology studies in both species and to provide information for dose-response relationships, toxicokinetic evaluations were conducted. In singlc-and multiple-exposure studies the toxicokinetics of... 

Epidemiological studies in occupationally-exposed pesticide workers typically involve exposure to a wide variety of pesticides. Therefore, it is impossible to ascribe the observed effects solely to maneb or mancozeb exposure. Additional epidemiological studies are necessary to more fully define the potenhal spectrum of systemic effects associated with these specific pesticides and to build a database from which dose-response relationships can be more fully defined. 

This chapter s characterization of lead as a neurotoxic hazard does not include detailed dose—response relationships with various levels of biomarkers such as PbB linked to various neurotoxic outcomes. The topics of dose/ exposure metrics and defining full-spectrum dose—response relationships are presented in the next part, the section dealing with the elements of human health risk assessment for environmental lead. Here, for ease of discussion, only a broad yardstick is provided for toxic lead exposures. Specifically, general PbB ranges associated with the various categories of lead neurotoxicity, especially in children, are noted. 

Stratification of lead s toxicity in humans into diagnosable disease or probabilistic risks of disease is not simply defined by where exposures and toxic effects align across the full spectrum of lead s dose—response relationships. That is, one cannot infer that only historic clinical effects at high Pb exposures comprise diagnosable disease and that subclinical effects always require population or epidemiological approaches. See the historical scientific perspective on these topics by Mushak (1992). 

A recent text illustrates the first example. The text reads "The relationship between exposure and the spectrum of effects is referred to as the "dose-response" and an understanding of this relationship constitutes a basis for the study of toxicity. By animal experimentation, dose-response curves have been developed for many chemicals, permitting the development of acceptable daily intakes (ADI) based on... 

Bellinger and Needleman (2003) reanalyzed their earlier cohort data, specifically stratifying the outcomes of the psychometric tests and dose—response strengths for 24-month PbB levels into those <10 pg/dl (N = 48) and those S 10 pg/dl. These authors reported that the dose—response slope, IQ loss versus PbB increase, was threefold steeper at PbB <10 pg/dl than for blood Pb values at 10 units or higher. This curvilinear relationship across the dose—response spectrum at lower versus higher dose has been documented in other individual and aggregated studies noted below. 

In brief, this relationship indicates that as dose increases above some threshold, effects get worse and more effects occur. This relationship has been a dictum of toxicology for centuries and still apphes across the whole dose—response spectrum for lead. Presented here is the chronology of dose—response thresholds in PbB from the onset of adverse health effects in terms of minimal amount of exposure assumed to produce such toxicity. 

Erythrocyte stability and survival are also affected by lead even in the absence of any genetic disorders predisposing to reduced erythrocyte survival and stability. Shortened erythrocyte life span, associated increase in reticulo-cytosis, and lead-impaired heme and globin synthesis collectively work to produce a lead-associated anemia, largely at the relatively high values of PbB encountered in occupational Pb contact (see, for example, U.S. EPA, 1986, Ch. 12). Genetically induced anemia in individuals also at risk for Pb-induced anemia would, in theory, further aggravate the reliability of the dose portion of dose—toxic response relationships across the spectrum of toxicity. 

Table 22.3 presents the full-spectrum of dose—toxic response relationships for lead toxicity in adults in terms of lowest reported adverse effect level thresholds. As with the earlier tables, only the lowest values for PbB in the associations specific for the indicated range are identified. It is also understood with these adult tabulations that as PbB values rise above lowest levels of determined associations, those toxic effects increase in severity and multiplicity. Toxicity criteria for reliability and validity parallel those enumerated for the earlier childhood tables. A number of dose-responses scaled to dose/exposure are identified in the table. In many cases, including hematotoxicity, peripheral neurotoxicity, and nephrotoxicity, effects are qualitatively similar but occur at higher empirically measured thresholds. 

In summary, changes or transition regions in a spectrum of relationships between biological quantities can have a profound impact upon the toxic response elicited by exogenous chemicals. The range of dose levels within which a transition occurs in the relationship between biological quantities and the dose level of a chemical constitutes a threshold region. 

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