Toxicity testing recommended

There are a number of examples in which histopathology and the functional immuno-toxicity tests recommended by regulatory guidance documents would not detect known... 

Acute Dermal Toxicity Test, Recommended Guideline, Interagency Regulatory Liaison Group Testing Standards and Guidelines Work Group, January 1981. 

Table 10.2 Plant species for toxicity testing recommended by international organisations...

TABLE 4-2 Summary of Toxicity Tests Recommended for Different Levels of Concern of Food Ingredients... 

Daylight fluorescent pigments (qv) are considered to be nontoxic. Since they are combinations of polymers and dyestuffs, the combined effect of the ingredients must be taken into account when considering the net toxic effect of these materials. Table 5 gives results of laboratory animal toxicity tests of standard modified melamine—formaldehyde-type pigments, the Day-Glo A Series, and the products recommended for plastic mol ding, Day-Glo Z-series. 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

European Centre for the Validation of Alternative Methods (ECVAM), six in vitro systems for chronic neurotoxicity testing are recommended for further consideration (Worth and Balls 2002). These are described as in vitro models that may be suitable for long-term toxicity testing. The systems are... 

The effectiveness of the insect toxicant aldrin to a wide variety of cotton pests has been determined through a large number of field tests. As a result of these tests, recommendations have been published suggesting the use of a mixture of 2.5% aldrin and 5%... 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. In the context of new chemical entities (NCEs, i.e. low molecular weight traditional chemicals), not only can the drug itself exhibit a toxic effect, but so potentially can drug breakdown products. As proteins are degraded to amino acids, any potentially toxicity associated with protein-based drugs is typically associated with the protein itself and not degradation products. 

Data for PCP and terrestrial wildlife are incomplete and — in view of the large interspecies variations in sensitivity — need to be collected. Research is needed on reproductive effects in animals following inhalation exposure to PCP additional acute and intermediate toxicity testing chronic duration exposure studies on cancer induction, genotoxicity, and immunotoxicity and the development of alternate biomarkers of PCP exposure and antidotes (WHO 1987 USPHS 1994). Until the results of these studies become available, it seems reasonable to apply to wildlife the same levels recommended for human health protection. 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

Most microalgal toxicity tests procedures recommend the use of initial cellular concentrations of 104 cells mL 1. This cellular concentration should be selected because it is the minimum cellular concentration that can be measured in haematocytometers (Neubauer chambers). Furthermore, natural cellular concentrations in non-polluted conditions (in marine environments) are often below the concentration mentioned. The importance of cellular density at the beginning of the test has been demonstrated for certain toxicants [43]. The lower the cellular concentration, the higher the sensitivity of the test, at least for certain types of xenobiotics, such as heavy metals. 

In Estonia the monitoring of effluents is based on chemical analysis. The list of controlled water quahty parameters depends on the type of industry. Bioassays are not used as a monitoring tool. However, according to HELCOM Recommendations No. 16/5, Requirement for discharging of waste water from the chemical industry, and No. 16/10, Reduction of discharges and emission from production of textiles, the toxicity effect of discharges into water bodies should be determined by (at least) two toxicity tests, which could be chosen out of the following four toxicity tests [203] ... 

A Guidance Document on Acute Inhalation Toxicity Testing is being developed and presently exists as a draft (OECD 2004b). The document recommends the Acute Toxic Class (ATC) Method with a group size of three animals per sex, if the objective of the test is solely related to hazard classification. Limits for particle-size distribution of aerosolized test substances are suggested. The preferred mode of exposure is the nose-only, head-only, or head/nose-only exposure technique, because this mode of exposure minimizes exposure or uptake by noninhalation routes. 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, while in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. 

Less complex test systems, including nonmammalian and in vitro cultures, are recommended only for pre-screening or secondary studies to elucidate mechanisms. A useful statement for use with lACUC committees comes from this section, as follows In short, there are no alternative test systems to whole animals currently available for reproduction toxicity testing with the aims set out in the introduction. ... 

It is recommended that testing be performed in the most relevant species, and that laboratory species and strains which are commonly used in prenatal developmental toxicity testing be employed. The preferred rodent species is the rat and the preferred nonrodent species is the rabbit. Justification should be provided if another species is used (4). 

Prenatal developmental toxicity testing of chemicals and pesticides requires evaluation of both cartilaginous and ossified skeletal components, but the corresponding testing guidelines do not specify how. Double staining is the preferred method and is strongly recommended. 

Balls M, Blaauboer B, Brusick D, Frazier J, Lamb D, Pemberton M, Reinhardt C, Roberfroid M, Rosenkranz H, Schmid B, Spiehnarm H, Stammati A-L, Walum E (1990) Report and recommendations of the CAAT/ ERGATT workshop on the validation of toxicity test procedmes. Altern Lab Anim 18 313-337... 

Before beginning a toxicity testing program, each of the procedures that are recommended must first be tested at the water-treatment site (sample-collection site) to ensure the adequacy of the concentration method (e.g., solubility of the components, minimization of artifacts, development of a quality assurance program). A mass balance based upon total organic carbon (TOC) is desired during this initial testing phase. 

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