Toxicity delayed neurotoxicity

Bioconcentration Carcinogenicity Reproductive toxicity Delayed neurotoxicity Biodegradation Ecosystem level Biodiversity degradation... 

Starvation or disease can lead to rapid release of the stored xenobiotic and to delayed toxic effects. In one well-documented case in the Netherlands (see Chapter 5), wild female eider ducks (Somateria mollissima) experienced delayed neurotoxicity caused by dieldrin. The ducks had laid down large reserves of depot fat before breeding, and these reserves were run down during the course of egg laying. Dieldrin concentrations quickly rose to lethal levels in the brain. Male eider ducks did not lay down and mobilize body fat in this way and did not show delayed neurotoxicity due to dieldrin. 

The rapid growth in the use of OPs and the proliferation of new active ingredients and formulations was not without its problems. Some OPs proved to be too hazardous to operators because of very high acute toxicity. A few were found to cause delayed neurotoxicity, a condition not caused by ChE inhibition (e.g., mipafox, lepto-phos). There was also the problem of the development of resistance, for example, by... 

No NOAELs or LOAELs were identified for toxic effects in humans after inhalation exposure to organophosphate ester hydraulic fluids. Reliable NOAELs and LOAELs for acute inhalation exposure are restricted to 4-hour NOAELs for systemic effects in rats exposed to Fyrquel 220 or Durad MP280 and 4-hour LOAELs for mild lethargy in rats exposed to Durad MP280 and Fyrquel 220 (Gaworski et al. 1986). The study identifying these NOAEL and LOAEL values did not measure cholinesterase inhibition, did not allow sufficient follow-up time for the development of delayed neurotoxic effects, and used a... 

Chemiak MG. 1988. Toxicological screening for organophosphorus-induced delayed neurotoxicity Complications in toxicity testing. Neurotoxicology 9 249-272. 

In addition to these standard acute toxicity studies, the OECD, US-EPA, and EU have developed a specific test guideline for delayed neurotoxicity of organophosphorus substances in the domestic laying hen following acute exposure, see Table 4.6. 

Cherniak MG Toxicological screening for organophosphoms-induced delayed neurotoxicity complications in toxicity testing. Neurotoxicology 2 9-271, 1988... 

The ideal animal for studying organophosphates would be one without hair, fur or feathers capable of contracting delayed neurotoxicity. Such a creature is the scaleless chicken, a mutant with a defect in feather and scale development (2,3), developed and maintained by Dr. Ursula K. Abbott of the Department of Avian Sciences, University of California, Davis. (Figure 3) Its absence of feathers makes it an excellent animal for studies of dermally applied toxicants. Renden and Abbott found that the scaleless mutant was more sensitive to applications of trithion in mineral oil than were either normal chickens or another mutant "ichthyiotic", in a study of mineral oil-induced dermatitis ( ). 

Studies on the scaleless chicken are underway examining its suitability as a model for assessing toxicity of organophosphates. The first compound selected for field trials was the defoliant DEF (S,S,S-tributylphosphorotrithioate) used during the harvesting of cotton in California and Arizona in the fall (October-November) when air movements are frequently restricted by inversions. DEF has been the subject of sufficient complaints to place it on the pre-RPAR list, although there are no reports of acute or delayed neurotoxicity in humans when it and related chemicals are used according to recommendations. It both inhibits cholinesterases and causes delayed neurotoxicity in hens (3,6). 

Toxicity The acute oral LD50 for rats ranges between 250 and 800 mg/kg, for mice between 715 and 870 mg/kg, and for guinea pigs 500 mg/kg. The acute dermal LD50 for rats and mice is more than 890 and 3,000 mg/kg, respectively. The acute inhalation LC50 in rats is reported as 5 mg/L. Sumithion 50-EC has been shown to cause delayed neurotoxicity in adult rats as well as in humans.57-60... 

Henderson, J.D., RJ. Higgins, L. Rosenblatt and B.W. Wilson. 1989. Toxicity Studies on Agent GA Delayed Neurotoxicity - Acute and Repeated Exposures to GA (Tabun). Einal Report, U.S. Army Medical Research and Development Command, Fort Detrick, MD. 

No clinical or experimental evidence is available to indicate that VX causes delayed neuropathy in humans (Munro et al., 1994). Chickens injected subcutaneously with supralethal doses of VX (10, 100, or 150 /rg/kg, following treatment with antidotes to protect against acute toxicity) exhibited no signs of a delayed neurotoxic response (Goldman et al., 1988). However, QL, a chemical intermediate of VX, has been reported to cause delayed neurotoxic effects in hens dosed at 635 mg/kg (Olajos et al., 1986). The available data indicate that delayed neuropathy in humans exposed to VX is unlikely. 

US Environmental Protection Agency (USEPA) (1998). Health effects test guidelines OPPTS 870.6100. Acute and 28-day delayed neurotoxicity of organophosphorous substances. EPA 712-C-98-237. Office of Prevention, Pesticides and Toxic Substances, US Environmental Protection Agency, Washington, DC. 

OPs are known to induce time-delayed neurotoxicity. This is due to the inhibition of an esterase in nerve tissue, neuropathy target esterase (NTE), that is also found in muscle and blood cells. The NTE level in the blood is an indicator of the inhibition of the enzyme. Inhibition of NTE and aging, the process of following the OP binding to an active esterase site that prevents the reactivation of the site, is important for selection of an antidote against certain OP nerve agents. It is of primary concern for Novichok agent. There is little information available on OP-caused neurotoxicity and the cardiac toxicity. 

Cholinesterase inhibition can sometimes persist for weeks thus, repeated exposures to small amounts of this material may result in accumulation of acetylcholinesterase inhibition with possible sudden-onset acute toxicity. Chlorpyrifos may be capable of causing organophosphate-induced delayed neurotoxicity in humans a massive overdose resulted in signs characteristic of delayed neurotoxicity. Animal studies generally indicate, however, that doses several times higher than the LD50 would be required to initiate delayed neurotoxicity. 

The acute oral and dermal LD50 values in rats and mice range from 1 to 12gkg . Domestic animals exhibit similar signs of cholinergic toxicity as seen in humans. Chickens may be somewhat more sensitive to acute toxicity from malathion exposure, but delayed neurotoxicity is not caused by this agent. 

As with most organophosphorus insecticides, acute toxicity is predominant. However tolerance to repeated exposures can occur. The no-observed-adverse-effect level (NOAEL) established from a rabbit developmental toxicity study was 50 mg kg day based on maternal toxicity (i.e., reduced body weight gain). Developmental toxicity studies were negative in rats and rabbits. A two-generation reproductive toxicity study in rats showed no increased sensitivity in pups compared to dams. Repeated exposure to malathion does not cause delayed neurotoxicity. The NOAEL of 2.4 mg kg day was established based on plasma cholinesterase inhibition in a long-term dosing study in rats. 

With repeated exposures, acetylcholinesterase inhibition can persist without indications of toxicity. In most cases, cholinesterase inhibition is without overt effects. Methyl parathion cannot cause delayed neurotoxicity. 

The term delayed neurotoxicity may be used to describe any type of toxicity to the nervous system involving a delay between the precipitating chemical exposure and the appearance of neurological signs or symptoms. However, this designation usually refers to organophosphorus (OP) compound-induced delayed neurotoxicity (or delayed neuropathy) (OPIDN), also known as OP compound-induced delayed polyneuropathy (OPIDP). 

Cisplatin and related compounds have also been evaluated in the management of metastatic melanoma. The effectiveness of platinum compounds as single agents is limited, with response rates reported to be less than 10%. The toxicities of cisplatin can be problematic, and include acute and delayed nausea and vomiting, renal toxicity, and neurotoxicity. 

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