Chronic risk assessment

PBPK models rely on a series of simultaneous differential equations that simulate chemical delivery to tissues via the arterial circulation and removal via the venous circulation. The models are run in time steps such that the entire course of chemical disposition can be presented for calculation of the area-under-the-curve (AUC) dose, often a key metric for chronic risk assessment. The physiologic parameters can be adapted for different species, sexes, age groups, and genetic variants to facilitate extrapolation from one type of receptor to another. 

Chronic risk assessment used an estimated NOEL of 0.02 mg/kg-d, for brain AChE inhibition, from a 1-yr. dog, dietary study. 

Chronic. Continuous exposure occurs over long periods of time, generally several mondis to years. Concentradons of inlialed (toxic) contaminants are usually reladvely low. This subject area falls in die general domain of healdi risk assessment (HRA) and it is diis subject tliat is addressed in die next five chapters. Thus, in contrast to the acute (short-term) exposures dial predominate in hazard risk assessments, cliroiiic (loiig-temi) exposures are the major concern in health risk assessments. 

Before leaving tliis introductory section, tlie reader is again reminded of tlie difference between healtli risk assessment (HRA) and liazard risk assessment (H2RA). Unfortunately, both terms have been used interchangeably by researchers and industrial persomiel. As indicated above, tliis Part of tlie book will address chronic health problems (HRA) while Part IV and V will be primarily on acute health problems (HZRA),... 

The reader should note tliat since many risk assessments have been conducted on the basis of fatal effects, there are also uncertainties on precisely what constitutes a fatal dose of thennal radiation, blast effect, or a toxic chemical. Where it is desired to estimate injuries as well as fatalities, tlie consequence calculation can be repeated using lower intensities of exposure leading to injury rather titan dcatli. In addition, if the adverse healtli effect (e.g. associated with a chemical release) is delayed, the cause may not be obvious. Tliis applies to both chronic and acute emissions and exposures. 

The more difficult thing is to develop models that can, with reasonable confidence, be used to predict ecological effects. A detailed discussion of ecological approaches to risk assessment lies outside the scope of the present text. For further information, readers are referred to Suter (1993) Landis, Moore, and Norton (1998) and Peakall and Fairbrother (1998). One important question, already touched upon in this account, is to what extent biomarker assays can contribute to the risk assessment of environmental chemicals. The possible use of biomarkers for the assessment of chronic pollution and in regulatory toxicology is discussed by Handy, Galloway, and Depledge (2003). 

Staples C, Mihaich E, Carbone J, Woodbum K, Klecka G (2004) A weight evidence analysis of the chronic ecotoxicity of nonylphenol athoxylates, nonylphenol ether carboxylates, and nonylphenol. Hum Ecol Risk Assess 10 999-1017... 

In Tables 14.9 and 14.10, the last column reports the environmental impact points (EIPs) for typical applications of organic and conventional pesticides derived from the Pesticide Environmental Assessment System, or PEAS. This model produces relative rankings of risks based on defined use rates and use patterns (the formulation used to apply a pesticide, timing, target of the application, spray equipment used, etc). PEAS scores reflect an equal balancing of acute pesticide risks to farm workers, chronic risks via dietary exposure and exposures to birds, Daphnia and bees. 

For similar reasons, chronic toxicity tests are probably less relevant for use in environmental risk assessment because of the significant discrepancy between the duration of exposure in the laboratory (many days to weeks) and field (usually 1 day or less - see Sect. 5). Sensitivity profiles for chronic toxicity are similar to acute toxicity, although, as would be expected, chronic endpoints are lower than the acute endpoints. Chronic toxicity endpoints for SPs are summarized in Table 3. 

Environmentally Induced Illnesses Ethics, Risk Assessment and Human Rights. Thomas Kerns, Jefferson, NC McFarland, [in press]. Addresses the ethics of managing environmental health and ubiquitous toxicants (such as solvents, pesticides and artificial fragrances). The work includes recent medical literature on chronic health effects from exposure to toxicants and the social costs of these disorders relevant historic and human rights documents recommendations for public policy and legislation and primary obstacles faced by public health advocates. 

In animal experiments exposures can be carefully controlled, and dose-response curves can be formally estimated. Extrapolating such information to the human situation is often done for regulatory purposes. There are several models for estimating a lifetime cancer risk in humans based on extrapolation from animal data. These models, however, are premised on empirically unverified assumptions that limit their usefulness for quantitative purposes. While quantitative cancer risk assessment is widely used, it is by no means universally accepted. Using different models, one can arrive at estimates of potential cancer incidence in humans that vary by several orders of magnitude for a given level of exposure. Such variations make it rather difficult to place confidence intervals around benefits estimations for regulatory purposes. Furthermore, low dose risk estimation methods have not been developed for chronic health effects other than cancer. The... 

In this paper I have tried to show that measurement of health benefits attributable to TSCA is not feasible. I hope that in doing so I have not belabored the obvious. For new chemicals and for most existing chemicals, prospective evaluation of health benefits to be achieved by various exposure controls will have to be based on extrapolation from microbial and animal data. However, while such extrapolation may be useful in a qualitative sense, quantitative risk assessment techniques involve considerable uncertainty, and in any case have not been developed for chronic effects other than cancer. 

For risk assessment purposes, the relative potency of AP and APEO has been evaluated by several authorities, initially on the basis of aquatic toxicity. In the UK, the Environment Agency used a QSAR approach [26] to derive the potencies listed in Table 7.3.2. Environment Canada used two approaches to characterise risks of NP, NPEO, and NPEC [27]. In the distributional approach, relative toxicities were proposed based on categorising acute and chronic toxicities. These are listed in Table 7.3.2. In addition a conservative approach was used. 

Effects assessment, by, as in the case of risk assessment for chemicals and pesticides, determining a set of marker organisms (including algae, zebrafish, insect larvae, benthic worm, water flea, etc.) that represent ecosystem components and food networks and are used to indicate acute and chronic effects. This step is also used to define the predicted no-effect concentrations (PNECs). 

Despite this clearly outlined procedure, scientific progress in the field has been slow, as very few authors have as yet attempted environmental risk assessment of PhCs in water, focussing their attention, furthermore, mainly on parent compounds rather than their metabolites, on the effects of individual substances rather than mixtures on target organisms and on acute rather than chronic toxicity. In particular, metabolite analysis tended to be disregarded as their exposure is very difficult to assess due to a lack of consensus in the literature regarding excreted metabolite fractions moreover, analysis has shown that their relative contribution to the overall risk is typically low [99]. 

In conclusion, the authors of the cited studies all agree that further research into environmental risk assessment of hospital effluents, incorporating different types of substances used in care and diagnostic activities, as well as cleaning operations (pharmaceuticals, detergents, disinfectants, heavy metals, macropollutants), is vital. Moreover, further studies need to be focussed on evaluating the risk posed by pollutant mixtures, and work is needed to validate the predictive models proposed thus far [19, 49], to evaluate chronic toxicity due to PhCs and then-mixtures and to provide experimental data pertaining to specific case studies. 

Finally, an equally Important component of ground water risk assessment Is toxicity. Only rarely have levels of pesticides In well water been detected which would cause acute toxicity, unless Improper disposal caused the contamination. Rather, as can be seen In Table III, the pesticide levels are usually In the low ppb range. Therefore, our current toxicity concerns are usually for chronic human toxicity or, occasionally, aquatic toxicity. There Is also the possibility of organisms receiving toxic amounts of pesticide residues over time via blomagnlf1catIon. 

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