Acute toxicity tests, discussion

Category A lists three types of studies for human health effects basic acute toxicity tests, a 28-day animal study (referred to in other discussions as a "sub-chronic" test), and a series of two (or more) screening tests for mutagenicity and carcinogenicity. 

In the pharmaceutical industry, acute toxicity testing has uses other than for product safety determinations. First, as in other industries, acute toxicity determinations are part of industrial hygiene or occupational health environmental impact assessments (Deichmann and Gerarde, 1969). These requirements demand testing not only for finished products but frequently of intermediates as well. These issues and requirements, however, are discussed in Chapter 2 and are not directly addressed here. 

Discuss two major problems in conducting acute toxicity tests with aquatic vertebrates and macroinvertebrates. 

As discussed above, luminescent bacteria have been used successfully to measure acute toxicity of chemicals and oivironmental samples. In addition to acute toxicity testing, chemicals and environmental samples are often tested for potential genotoxicity. There are several validated methods in routine use for assessing genotoxicity of chemicals but they have been practical limitations. These limitations include high cost per test sample and complex protocols which necessitate highly trained personnel to obtain reproducible test data, and to provide reliable interpretation. 

As mentioned previously (and discussed in detail in Sec. IX), contact lens products have specific guidelines that focus on compatibility with the contact lens and biocompatibility with the cornea and conjunctiva [75], These solutions are viewed as new medical devices and require testing with the contact lenses with which they are to be used. Tests include a 21-day ocular study in rabbits and employ the appropriate types of contact lenses with which they are to be used and may include the other solutions that might be used with the lens. Additional tests to evaluate cytotoxicity potential, acute toxicity, sensitization potential (allergenicity), and risks specific to the preparation are also required [75-77], These tests are sufficient to meet requirements in the majority of countries, though testing requirements for Japan are currently much more extensive. 

In 1998, two bioassay methods were considered by the Chilean Regulation Institute (INN) as the first attempts for the introduction of microbioassays for routine testing in Chilean regulations (1) the Bacillus subtilis growth inhibition test for toxicity evaluation of industrial effluents discharged into sewers, to detect interference with the BOD, is near endorsement and (2) the assessment of acute toxicity in receiving waters using D. pulex is presently under discussion. 

In rats, guinea pigs and other test animals, acute yellow atrophy and other liver changes have been observed in feeding and inhalation experiments. Exposure of rabbits to hepta- and octaCNs at 500 mg kg 1 bw resulted in death of all individuals and one of three individuals exposed to pentaCNs. No mortality occurred in rabbits given mono-, di- or tetraCNs for 7 days [43]. Most of the toxic effects discussed above were associated with penta- and hexaCNs. 

Due to the high doses necessary for acute effects as observed in short-term toxicity tests and to the lack of effects seen at earlier time-points in long-term studies, only chronic reference doses are used in conjunction with exposure for the calculation of triazine dietary risk. Therefore, the remainder of this discussion is limited to chronic exposure and risk. 

This section addresses the use of acute and chronic toxicity data in classification, and special considerations for exposure regimes, algal toxicity testing, and use of QSARs. For a more detailed discussion of aquatic toxicity concepts, one can refer to Rand (1996). 

In the past, many industrial effluents were significantly toxic so that tests relying on acute toxicity to fish were routinely used these usually involved exposure to the toxicant for a maximum of 96 h. Rainbow trout were traditionally used and the results were reported as LD50 values. With increased demand for less toxic effluents before discharge into aquatic systems and increased appreciation of the complexity of ecosystem effects (Rosenthal and Alderdice 1976), assays for acute toxicity have gradually been replaced by considerably more-sophisticated test systems. A review has been given that discusses not only the broad mechanisms whereby PAHs exert their toxicity on aquatic organisms, but the cardinal issue of bioavailability (van Brum-melen et al. 1998). 

The first component we will discuss is the assessment of actual hazard, usually done with laboratory animal tests. Depending on the regulatory agency involved, studies are done in the most sensitive animal species using the most discriminating test available. Such safety studies are usually conducted in at least two rodent species, and any evidence of toxicity determined. The strains of mice and rats used are sometimes dependent on the type of chemical to be tested. In reality a number of sequential studies are conducted to determine the acute toxic dose and to define a profile of the disease induced. For some compounds or endpoints, such as birth defects, other animal species may be used, such as dogs, monkeys, or rabbits. Longer studies are then conducted to determine so-called subchronic effects and help select the doses used for chronic studies. The aim of these experiments is to determine the no observed adverse effect level, the NOAEL. 

Nontechnical Summary In this paper, the process of risk assessment with compounds which exhibit chronic but not acute toxicity is first reviewed. The remainder of the paper is spent on reviewing the procedure for quantifying absorption through the skin. The test animal used is the rhesus monkey since previously published work has shown this animal to yield data most similar to man. Data are presented on oryzalin for which dermal absorption was less than 2 percent of the applied dose. The problems and shortcomings of the procedure as well as its advantage (similarity to man) are also discussed. 

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