Dose-response relationships exposure biomarkers

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. 

See also American Conference of Governmental Industrial Hygienists Biomarkers, Human Health Biotransformation Dose-Response Relationship Exposure Hazard Identification Medical Surveillance Occupational Safety and Health Administration Psychological Indices of Toxicity Risk Assessment, Ecological Risk Assessment, Human Health. 

Exposure. Measurement of total phenol in the urine is the most useful biomarker following inhalation exposure to phenol (ACGIH 1991). The test is nonspecific and should not be used when workers are exposed to benzene, to household products, or to medications containing phenol. Dermal exposure may also result in overestimation of inhalation exposure. In persons not exposed to phenol or benzene, the total phenol concentration in the urine does not exceed 20 mg/L and is usually <10 mg/L (ACGIH 1991). Phenol can also be measured in the urine after oral exposure, although a dose-response relationship between oral exposure to phenol and phenol in the urine has not been established. Benzene metabolism yields not only phenol, 1,4-dihydroxybenzene, and their sulfates and glucuronides, but also the benzene-... 

Exposure to toxic chemicals and the effect or response need to be quantitated to define the dose response relationship. These use what are called biomarkers, and new technology is constantly expanding the range of possible measurements. Susceptibility, important in risk assessment, can also be quantitated with biomarkers. 

There is a continuing need for validated biomarkers of exposure that provide information on the frequency, duration, and intensity of an exposure, as well as a better understanding of distribution, metabolism, and excretion within the individual. Likewise, continued development of analytical methods (e.g. Monte Carlo) that provide a broad characterization of exposure and dose-response relationships should be encouraged. 

There are currently no reliable data on the dose-response relationship of benzene exposure and chromosomal effects. In light of the data of Ward et al. (1992), further investigation of mutational effects at low doses seems appropriate. Additional data on the quantitative relationship between measured exposures and clastogenic effects might provide an alternative biomarker of effect. 

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". 

These models often incorporate intermediate biomarker responses. Consequently, trial simulations driven by PK models, rather than more traditional dose-response relationships, will enable more detailed simulations. For example, exposure differences due to interactions, inclusion of special populations, or from dosing regimen or formulation changes may be explored with the PK models driving PD responses. This will place additional emphasis on the modeler to develop reliable PK models using Phase 1 and 2 data that translate into the patient population. Appropriate consideration of covariates, as discussed later, will be an important part of this development. 

Several other studies published in the last 5 years have reported adverse associations between occupational lead exposure and impaired renal function. A study in Nigeria described impaired creatinine clearance in 190 lead workers (mean BLL 50 pg/dL) compared with 80 controls but did not adjust for aity covariates (Alasia et al. 2010). A study of 87 industrial workers (mean BLL 29 pg/dL) and 61 controls in Pakistan reported statistically significant correlations between BLL and seram creatinine, uric acid, and several early biologic markers of renal dysfunction (Khan et al. 2008). Early biologic markers of tubular and glomeralar function were explored in 155 battery workers (mean BLL 20 pg/dL) and 36 controls in China (Sun et al. 2008). The study reported a dose-response relationship between BLL and renal function, biomarkers of bone metabolism, and the prevalence of osteoporosis. Those and many other studies summarized by EPA (2012) have been rather consistent in making the link between occupational lead exposure and impaired renal function. 

Dose—response relationships for lead, in terms of PbB as the dose/ exposure biomarker or administered doses in experimental systems versus some adverse effect, are probably better known for lead than for virtually any other environmental contaminant and certainly for any other metal or metal-related pollutant. Furthermore, these relationships are buttressed by a vast scientific and pubhc health literature derived from clinical and epidemiological studies, experimental animal testings, and a large variety of sophisticated mechanistic toxicological studies in vivo and in vitro. 

Second, lead s kinetic behavior in vivo provides the means by which one can identify and exploit biomarkers of toxic lead exposures as well as determine the dose portion of critical dose—toxic response relationships for lead poisoning. Measurement of lead in whole blood and its relatively reliable use in determining both systemic lead exposure and the extent of toxic injury (dose—response relationships) is mainly feasible because we understand how Pb s toxicokinetic behavior in blood relates to the temporal and toxicological... 

PbP is a relatively rapid reflection of Pb uptake and distribution toxicokinetics in human populations (NAS/NRC, 1993 U.S. EPA, 2006) and is the in vivo medium by which Pb is excreted to urine through glomerular filtration in humans. This behavior in terms of rapid exchange of Pb with target tissues and PbP makes the latter a more temporally sensitive biomarker for toxicokinetics and toxicodynamics. Little has evolved in the more current toxicological literature on Pb to quantify dose—response relationships using PbP as the dose metric beyond attempts at elucidating the exposure marker trio of PbB, PbP, and Pb in bone. 

This chapter deals with epidemiological studies of human Pb exposure using biomarkers of such exposure. These studies deal with various parameters and correlates of human Pb exposure from demographic and environmental measurements. While much of the available data has been generated in the United States, illustrative international studies are also presented where relevant. Later chapters deal with epidemiological studies of dose—response relationships for Pb and an array of toxicity outcome measures addressing organ and tissue toxicides. 

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. 

A critical question in fetal Pb toxicokinetics is how one best measures dose—response relationships among various exposure biomarkers as well as relationships governing dose—toxic response relationships. It is now accepted that bone Pb is a better biomarker in constmcting dose—toxic response relationships for a variety of toxic effects than are indicators such as PbB. This was demonstrated in Chapter 13 describing cardiovascular effects of Pb. 

The size and quality of the available database for an environmental pollutant will vary greatly across substances and will also vary within the four components of the typical risk assessment. The variety of adverse health risks of a substance may be qualitatively well known, for example, but dose—response relationships may be poorly quantifiable because of either limits of inadequate exposure measurement data or absence of good biomarkers of adverse effect or absence of information on the full span of the dose—response curve. Hazard characterization and dose—response relationships may both be understood as general descriptors, but case-specific or scenario-specific exposure data may be lacking, requiring judgment about alternative approaches (e.g., default values). 

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