Biomarkers of Internal Dose

Cotinine levels in urine (a compound present in tobacco) 

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Pentachlorophenol concentrations in urine and serum can be used as biomarkers of internal dose (Colosio et al., 1993a). PCP concentrations up to about 30 mg/L were detected in urine samples of exposed workers, while concentrations lower than 0.3 mg/L were detected in the general population. The presence of PCP in biological samples of the general population is attributable to indoor exposure to the compound released from treated materials (furniture, leather, paints, etc.). 

Urinary 1-hydroxypyrene could be a suitable biomarker of internal dose of polycyclic aromatic hydrocarbons, as recently shown in carbon black workers, on the condition that both respiratory (including gaseous PAHs and particle-bound PAHs) and dermal exposures have been assessed (Tsai et al. 2002). Urinary 1-hydroxypyrene concentrations were higher among road pavers than among office workers serving as referents (Heikkila et al. 2002). 

Biomarkers of internal dose integrate all pathways of exposure by estimating the amount of a pesticide that is absorbed into the body via measurements of the pesticide, its metabolite, or its reaction product in biological media. The most studied biological samples have been urine and blood, but also breast milk, saliva, placenta, etc. Finally the biologically effective dose is the amount of a pesticide that has interacted with a target site and altered a physiological function, for example, the inhibition of cholinesterase enzymes or the development of DNA adducts. 

Biomarkers of exposure are important in toxicology, because they are indicators of internal dose, or the amount of chemical exposure that has resulted in absorption into the body. Biomarkers of effect reflect changes following exposure at different levels and their reversibility. Biomarkers of susceptibility represent an inherent property of the individual, due to environmental or genetic factors, that can be determined without exposure. Biomarkers play a role in the use of pharmacogenetics, pharmacogenomics, and pharmacoproteomics for development of personalized medicine. 

PAHs half-lives in humans are in fact in the range of days/hours, and metabolism is responsible of the formation of toxicologically active (carcinogenic) metabolites. Because of the laek of persistenee and to the complexity of PAH mixtures, human exposure is usually charaeterised in terms of internal dose rather than of body-burden , by the use of biomarkers of exposure, mainly 1-OH pyrene in urine and DNA adducts in peripheral blood l nnphoeytes. 

Biomarkers for internal close of the intoxicant—dose monitoring. Bioniarkers for early biological changes following exposure— effect... 

There is a growing need to better characterize the health risk related to occupational and environmental exposure to pesticides. Risk characterization is a basic step in the assessment and management of the health risks related to chemicals (Tordoir and Maroni, 1994). Evaluation of exposure, which may be performed through environmental and biological monitoring, is a fundamental component of risk assessment. Biomarkers are useful tools that may be used in risk assessment to confirm exposure or to quantify it by estimating the internal dose. Besides their use in risk assessment, biomarkers also represent a fundamental tool to improve the effectiveness of medical and epidemiological surveillance. 

Biomarkers are used at several stages in the risk assessment process. Biomarkers of exposure are important in risk assessment, as an indication of the internal dose is necessary for the proper description of the dose-response relationship. Similarly, biomarkers of response are necessary for determination of the no observed adverse effect level (NOAEL) and the dose-response relationship (see below). Biomarkers of susceptibility may be important for identifying especially sensitive groups to estimate an uncertainty factor. 

As stated in Chapter 1, biomonitoring in the context of this report is focused on biomarkers of exposure, that is, it is limited to the early stages in the process internal dose, biologically effective dose, and early biologic effect. 

Use animal PK modeling to convert the dose-response relationship seen in toxicity studies (applied dose) to a dose-response relationship based on internal dose, using a dose metric derived from human biomonitoring data. This approach fosters the development of a biomarker-response relationship and biomarker-based toxicity values. 

Develop biomarkers suitable for determining internal dose-response or excreted dose-response relationships in animal studies with confirmation of biomarker applicability to humans. 

The best opportunities for communicating health implications of biomonitoring data arise when an unequivocal internal dose-response relationship has been established for humans (by methods discussed in Chapter 5) or when a clinician has data on a person s health that can be used for context-setting. The first case applies primarily to group VII biomarkers (and, with caveats, to some group VI examples) the second case extends to group V biomarkers. 

Toxicologic studies need to be expanded to incorporate collection of biomonitoring data in animals that can be related to humans. Much of the dose-response information used in risk assessments is derived from animal toxicologic studies, and these do not collect information on internal dose. Therefore, dose-response relationships can be expressed only in terms of external dose (such as milligrams per kilogram per day). However, to interpret biomonitoring data, the relationship between internal dose (biomarker concentration) and effect must be understood. 

Biomarkers of exposure are an indicator of absorbed dose and may present unique advantages in exposure assessment. Biomarkers demonstrate that internal exposure has occurred and can be used to estimate chemical uptake over time and help establish the relationship between exposure and effect. They are apical in nature, in that they account for and integrate over all sources of exposure. Specifically in relation to potentially sensitive subpopulations like children, biomarkers may be able to identify increased absorption or biological response in comparison with the general population. Biomarker data alone cannot be used to establish source and route of exposure and are limited in providing information on frequency, duration, and intensity. Moreover, metabolism of any chemical... 

The urinary excretion of DNOC was also studied in these volunteers (King and Harvey 1953b). The 5 volunteers excreted about 7% of the total DNOC dose in the urine over 13 days after exposure. However, only 0.016% of the dose was excreted within 5 hours after exposure and 1.3% within 24 hours after exposure. In the first 24 hours after a single exposure of 75 mg per person, 35.2-46.6% of the dose could be accounted for by blood levels and 0.8-2.0% could be accounted for by urinary levels. Thus, 51.7-64.0% of the oral dose was unaccounted for. These data suggest that DNOC is stored longer in the human body than in the animal body. Since DNOC binds to albumin, the chief internal stores may be extracellular fluids containing albumin. Therefore, urinary levels of DNOC may not be useful biomarkers to quantitate exposure. 

Cadmium levels in blood are generally recognised as a biomarker of recent exposure to cadmium. It can also be used as biomarker of cumulative internal dose and accumulation of cadmium, buf only when fhere is long-term (decade long) continuous exposure, for example in subsistence farmers consuming their own crops. Cadmium levels in urine are a widely recognised biomarker of cumulative internal dose, kidney and body burden of Cd. Dose-response relationships between urinary Cd and occurrence of kidney effects are described in the subsequent sections of this chapter "Sweden", "Japan", "Belgium", and "Other countries". 

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