Framework for use of toxicity screening tools in context-based decision-making.

One of the principal applications of toxicology data is to inform risk assessments and support risk management decisions that are protective of human health. Ideally, a risk assessor would have available all of the relevant information on (a) the toxicity profile of the agent of interest; (b) its interactions with living systems; and (c) the known or projected exposure scenarios: to whom, how much, by which route(s), and how often. In practice, however, complete information is seldom available. Nonetheless, decisions still must be made. Screening-level assays and tools can provide support for many aspects of the risk assessment process, as long as the limitations of the tools are understood and to the extent that the added uncertainty the tools introduce into the process can be characterized and managed. Use of these tools for decision-making may be an end in itself for risk assessment and decision-making or a preliminary step to more extensive data collection and evaluation before assessments are undertaken or completed and risk management decisions made. This paper describes a framework for the application of screening tools for human health decision-making, although with some modest modification, it could be made applicable to environmental settings as well. The framework consists of problem formulation, development of a screening strategy based on an assessment of critical data needs, and a data analysis phase that employs weight-of-evidence criteria and uncertainty analyses, and leads to context-based decisions. Criteria for determining the appropriate screening tool(s) have been identified. The choice and use of the tool(s) will depend on the question and the level of uncertainty that may be appropriate for the context in which the decision is being made. The framework is iterative, in that users may refine the question(s) as they proceed. Several case studies illustrate how the framework may be used effectively to address specific questions for any endpoint of toxicity.

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Disinfection by-products (DBPs) are formed when disinfectants such as chlorine, chloramine, and ozone react with organic and inorganic matter in water. The observations that some DBPs such as trihalomethanes (THMs), di-/trichloroacetic acids, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) are carcinogenic in animal studies have raised public concern over the possible adverse health effects of DBPs. To date, several hundred DBPs have been identified. To prioritize research efforts, an in-depth, mechanism-based structure-activity relationship analysis, supplemented by extensive literature search for genotoxicity and other data, was conducted for ranking the carcinogenic potential of DBPs that met the following criteria: a) detected in actual drinking water samples, b) have insufficient cancer bioassay data for risk assessment, and c) have structural features/alerts or short-term predictive assays indicative of carcinogenic potential. A semiquantitative concern rating scale of low, marginal, low-moderate, moderate, high-moderate, and high was used along with delineation of scientific rationale. Of the 209 DBPs analyzed, 20 were of priority concern with a moderate or high-moderate rating. Of these, four were structural analogs of MX and five were haloalkanes that presumably will be controlled by existing and future THM regulations. The other eleven DBPs, which included halonitriles (6), haloketones (2), haloaldehyde (1), halonitroalkane (1), and dialdehyde (1), are suitable priority candidates for future carcinogenicity testing and/or mechanistic studies.

Occurrence, synthesis, and mammalian cell cytotoxicity and genotoxicity of haloacetamides: an emerging class of nitrogenous drinking water disinfection byproducts.

The haloacetamides, a class of emerging nitrogenous drinking water disinfection byproduct (DBPs), were analyzed for their chronic cytotoxicity and for the induction of genomic DNA damage in Chinese hamster ovary cells. The rank order for cytotoxicity of 13 haloacetamides was DIAcAm > IAcAm > BAcAm > TBAcAm > BIAcAm > DBCAcAm > CIAcAm > BDCAcAm > DBAcAm > BCAcAm > CAcAm > DCAcAm > TCAcAm. The rank order of their genotoxicity was TBAcAm > DIAcAm approximately equal to IAcAm > BAcAm > DBCAcAm > BIAcAm > BDCAcAm > CIAcAm > BCAcAm > DBAcAm > CAcAm > TCAcAm. DCAcAm was not genotoxic. Cytotoxicity and genotoxicity were primarily determined by the leaving tendency of the halogens and followed the order I > Br > > Cl. With the exception of brominated trihaloacetamides, most of the toxicity rank order was consistent with structure-activity relationship expectations. For di- and trihaloacetamides, the presence of at least one good leaving halogen group (I or Br but not Cl) appears to be critical for significant toxic activity. Log P was not a factor for monohaloacetamides but may play a role in the genotoxicity of trihaloacetamides and possible activation of dihaloacetamides by intracellular GSH and -SH compounds.

Haloacetonitriles vs. regulated haloacetic acids: are nitrogen-containing DBPs more toxic?

Haloacetonitriles (HANs) are toxic nitrogenous drinking water disinfection byproducts (N-DBPs) and are observed with chlorine, chloramine, or chlorine dioxide disinfection. Using microplate-based Chinese hamster ovary (CHO) cell assays for chronic cytotoxicity and acute genotoxicity, we analyzed 7 HANs: iodoacetonitrile (IAN), bromoacetonitrile (BAN), dibromoacetonitrile (DBAN), bromochloroacetonitrile (BCAN), chloroacetonitrile (CAN), dichloroacetonitrile (DCAN), and trichloroacetonitrile (TCAN). The cytotoxic potency (%C1/2 values) ranged from 2.8 microM (DBAN) to 0.16 mM (TCAN), with a descending rank order of DBAN > IAN approximately BAN > BCAN > DCAN > CAN > TCAN. HANs induced acute genomic DNA damage; the single cell gel electrophoresis (SCGE) genotoxicity potency ranged from 37 microM (IAN) to 2.7 mM (DCAN). The rank order of declining genotoxicity was IAN > BAN approximately DBAN > BCAN > CAN > TCAN > DCAN. The accompanying structure-activity analysis of these HANs was in general agreement with the genotoxicity rank order. These data were incorporated into our growing quantitative comparative DBP cytotoxicity and genotoxicity databases. As a chemical class, the HANs are more toxic than regulated carbon-based DBPs, such as the haloacetic acids. The toxicity of N-DBPs may become a health concern because of the increased use of alternative disinfectants, such as chloramines, which may enhance the formation of N-DBPs, including HANs.

The expanding role of predictive toxicology: an update on the (Q)SAR models for mutagens and carcinogens.

Different regulatory schemes worldwide, and in particular, the preparation for the new REACH (Registration, Evaluation and Authorization of CHemicals) legislation in Europe, increase the reliance on estimation methods for predicting potential chemical hazard. To meet the increased expectations, the availability of valid (Q)SARs becomes a critical issue, especially for endpoints that have complex mechanisms of action, are time-and cost-consuming, and require a large number of animals to test. Here, findings from the survey on (Q)SARs for mutagenicity and carcinogenicity, initiated by the European Chemicals Bureau (ECB) and carried out by the Istituto Superiore di Sanita' are summarized, key aspects are discussed, and a broader view towards future needs and perspectives is given.

Chemical and biological characterization of newly discovered iodoacid drinking water disinfection byproducts.

Iodoacid drinking water disinfection byproducts (DBPs) were recently uncovered in drinking water samples from source water with a high bromide/iodide concentration that was disinfected with chloramines. The purpose of this paper is to report the analytical chemical identification of iodoacetic acid (IA) and other iodoacids in drinking water samples, to address the cytotoxicity and genotoxicity of IA in Salmonella typhimurium and mammalian cells, and to report a structure-function analysis of IA with its chlorinated and brominated monohalogenated analogues. The iodoacid DBPs were identified as iodoacetic acid, bromoiodoacetic acid, (Z)- and (E)-3-bromo-3-iodopropenoic acid, and (E)-2-iodo-3-methylbutenedioic acid. IA represents a new class (iodoacid DBPs) of highly toxic drinking water contaminants. The cytotoxicity of IA in S. typhimurium was 2.9x and 53.5x higher than bromoacetic acid (BA) and chloroacetic acid (CA), respectively. A similar trend was found with cytotoxicity in Chinese hamster ovary (CHO) cells; IA was 3.2x and 287.5x more potent than BA and CA, respectively. This rank order was also expressed in its genotoxicity with IA being 2.6x and 523.3x more mutagenic in S. typhimurium strain TA100 than BA and CA, respectively. IA was 2.0x more genotoxic than BA and 47.2x more genotoxic than CA in CHO cells. The rank order of the toxicity of these monohalogenated acetic acids is correlated with the electrophilic reactivity of the DBPs. IA is the most toxic and genotoxic DBP in mammalian cells reported in the literature. These data suggest that chloraminated drinking waters that have high bromide and iodide source waters may contain these iodoacids and most likely other iodo-DBPs. Ultimately, it will be important to know the levels at which these iodoacids occur in drinking water in order to assess the potential for adverse environmental and human health risks.