Organ toxicity? neurotoxicity

Cumulative organ toxicity also presents a significant obstacle for effective chemotherapy. In many cases, the severity of the toxicity impedes the broader use of an agent. Other specific toxicities are associated with specific agents, for example cardiotoxicity with adriamycin (32), renal toxicity with i7j -platinum (28), and neurotoxicity with vincristine (49). 

Often several different toxic hazards (neurotoxicity, organ toxicity, developmental toxicity, for example) associated with the substance that is the subject of the risk assessment, each with its own dose-response characteristics, will emerge from the first two steps of the risk assessment. Which of these should become the principal basis for the final risk assessment. ... 

The TGD (EC 2003), Chapter 3.9, addresses repeated dose toxicity and provides guidance on data requirements, evaluation of data, and dose-response assessment. Included is a section on specific system/organ toxicity dealing with guidance on investigation of neurotoxicity (Section 4.7.7.3) and... 

Reactive chemicals or their reactive intermediates, such as free radicals and other electrophilic species, may form essentially irreversible covalent bonds with adjacent macromolecules, such as proteins, lipids, and DNA, resulting in the formation of adducts. Covalent adducts can disrupt the normal function of such macromolecules and result in a broad spectrum of toxic responses. These may range from localized transient skin irritation to systemic target organ toxicity (such as hepatotoxicity, neurotoxicity, and renal toxicity), genotoxicity, or carcinogenicity. 

Organ toxicity considers effects at the level of organ function (neurotoxicity, hepatotoxicity, nephrotoxicity, etc.). 

Mechanism of action can be an important factor determining selectivity. In the extreme case, one group of organisms has a site of action that is not present in another group. Thus, most of the insecticides that are neurotoxic have very little phytotoxicity indeed, some of them (e.g., the OPs dimethoate, disyston, and demeton-5 -methyl) are good systemic insecticides. Most herbicides that act upon photosynthesis (e.g., triaz-ines and substituted ureas) have very low toxicity to animals (Table 2.7). The resistance of certain strains of insects to insecticides is due to their possessing a mutant form of the site of action, which is insensitive to the pesticide. Examples include certain strains of housefly with knockdown resistance (mutant form of Na+ channel that is insensitive to DDT and pyrethroids) and strains of several species of insects that are resistant to OPs because they have mutant forms of acetylcholinesterase. These... 

The priority effects are carcinogenicity, mutagenicity, reproductive or developmental toxicity, endocrine disruption and neurotoxicity. Human toxicity is broader than priority effects, including acute toxicity, systemic toxicity (organ effects), immune system effects and skin/eye/respiratory damageaswellasthepriority effects. And toxicity as T includes both human toxicity and ecotoxicity. 

No data were located regarding toxic effects in humans following oral exposure to polyalphaolefin hydraulic fluids. No deaths or body weight changes occurred in rats in a series of acute lethality studies with nine polyalphaolefin hydraulic fluids at doses ranging from 4,250 to 5,000 mg/kg. One of these fluids was also tested for neurotoxicity in chickens, and did not produce effects at 4,250 mg/kg. The available data have not identified a target organ or effect for these fluids. The data are inadequate for MRL derivation. No intermediate or chronic oral MRLs for polyalphaolefin hydraulic fluids were derived due to the lack of data. 

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