Toxic potential human risk

Confusion often occurs with the use of the terms exposure , concentration , and dose . Dose is the amount of contaminant that is deposited or absorbed in the body of an exposed individual over a specific duration. Dose occurs as a result of exposure. Concentration is that level of contaminant present in the air potentially available to be inhaled. The atmospheric concentration of a chemical by itself does not define the total dose of a chemical delivered or the specific sites of potential injury. For a substance present in inhaled air to be toxic, a significant dose must first be removed from the inhaled air and be deposited on sensitive tissue. Knowledge of the dose to initial target sites provides a critical link between exposure and the subsequent biological response. Understanding the disposition of inhaled xenobiotics is complex and, due to space limitations, cannot be described in detail here. However, certain basic concepts need to be presented to provide information on the various factors related to exposure, dose, and response that are fundamental to understanding the potential human risk from inhaled chemical agents. 

Assessment of the immimogenic consequences of gene delivery should also be possible in the chosen species this is particularly important for the evaluation of viral vectors. There has been much discussion on the value of using a permissive host to assess potential human risk from these vectors. The natural route of exposure - i.e. respiratory for adenoviruses - traditionally used to assess permissivity, seems unnecessary to assess the safety of gene therapy products, particularly with the core study approach discussed above. Systemically-administered replication-competent adenovirus will infect (i.e. gain entry into the cell) and be pathogenic in numerous tissues (Duncan et al., 1978). Gene expression and viral replication depend on the species, route of exposure, and individual tissue susceptibility (Torres et al., 1996 Bett et al., 1962). Thus i.v. administration of viral vectors to mammalian test species should permit the evaluation of potential toxicity of widely-distributed vectors. 

Generally, the main pathways of exposure considered in tliis step are atmospheric surface and groundwater transport, ingestion of toxic materials that luu c passed tlu-ough the aquatic and tcncstrial food chain, and dermal absorption. Once an exposure assessment determines the quantity of a chemical with which human populations nniy come in contact, the information can be combined with toxicity data (from the hazard identification process) to estimate potential health risks." The primary purpose of an exposure assessment is to... 

This section describes how the tj pes of to.xicity inforniation arc considered in the to.xicity assessment for carcinogenic effects. A slope factor and the accompanying weight of evidence determination are the toxicity data most commonly used to evaluate potential human carcinogenic risks. The methods the USEPA uses to derive these values arc outlined below. 

Tables 2.6 and 2.7 give examples of the modes of action of pollutants in animals and in plants/fungi, respectively. It is noteworthy that many of the chemicals represented are pesticides. Pesticides are designed to be toxic to target species. On the other hand, manufacturers seek to minimize toxicity to humans, beneficial organisms and, more generally, nontarget species. Selective toxicity is an important issue. Regardful of the potential risks associated with the release of bioactive compounds into the environment, regulatory authorities usually require evidence of the mode of toxic action before pesticides can be marketed. Other industrial chemicals are not subject to such strict regulatory requirements, and their mode of action is frequently unknown.

Hertwich EG, Mateles SF, Pease WS, McKone TE (2001) Human toxicity potentials for life cycle assessment and toxics release inventory risk screening. Environ Toxicol Chem 20 928-939... 

Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

Toxicity and exposure studies indicate PFOA is immunosuppressive and can cause developmental problems and other adverse effects in laboratory animals, such as rodents [Lau et al (2004), Lau et al (2006)]. In 2005 the US Environmental Protection Agency (EPA) released a draft risk assessment of its potential human health effects [U S. EPA (2005)]. A subsequent review by the EPA science advisory board concluded that there is sufficient evidence to classify PFOA as likely human carcinogenic. 

For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires experienced scientific judgment. The toxicity data from animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, the data from the most sensitive animal species are used to set AEGLs. Uncertainty factors are commonly used when animal data are used to estimate minimal risk levels for humans. The magnitude of uncertainty factors depends on the quality of the animal data used to determine the no-observed-adverse-effect level (NOAEL) and the mode of action of the substance in question. When available, pharmocokinetic data on tissue doses are considered for interspecies extrapolation. 

The contact of nanoparticles with human skin is another concern when considering the potential human health risks of CNTs (Nohynek et al., 2007). It can penetrate the skin, reach to bloodstream, and be taken by cells, tissues, and organs. For example, if gloves are not worn when handling CNTs, dermal toxicity can take place and very fine nanoparticles might also penetrate the skin through resulting in transdermal delivery. 

Carbaryl is perhaps one of the best studied of the major lawn chemicals, and evidence of health-related risks related to its use date as early as the late 1960s, when studies of the chemical revealed both its toxicity and its potential impact on animal (and potentially human) reproduction. In 1969 the U.S. Department of Health Education and Welfare recommended restrictions on the use of the chemical, owing to mounting evidence that it may be tetragenic (causing birth defects). Later research in the 1980s pointed towards the possible implication of carbaryl in neurotoxicity, brain function, and aggressive behavior. ... 

Chemical-induced reproductive toxicity consists of effects on reproductive performance (e.g., fertility and fecundity), the reproductive tract, and/or sexual development. Reproductive toxicity has been routinely assessed, using laboratory animal studies, in the chemical risk assessment process for over 40 years. For environmental chemicals, the multigeneration reproduction and fertility study in rats has been the primary tool for assessing reproductive toxicity potential in humans. Unfortunately, these expensive and animal-intensive studies have only been conducted on a fraction of environmentally... 

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