Delayed neurotoxicity

Phosphonothioate Esters of Phenols. Phosphonates with a single P—C bond are highly toxic and persistent iasecticides but have not been used extensively because some compounds produce delayed neuropathy leading to irreversible paralysis ia higher animals, including humans. Such compounds specifically inhibit an enzyme, neurotoxic esterase, that is responsible for the growth and maintenance of long nerve axons (31,32). 

Hansen LG. 1983. Biotransformation of organophosphorus compounds relative to delayed neurotoxicity. Neurotoxicology 4 97-111. 

Ohkawa H, Oshita H, Miyamoto J. 1980. Comparison of inhibitory activity of various organophosphorus compounds against acetylcholinesterase and neurotoxic esterase of hens with respect to delayed neurotoxicity. Biochem Pharmacol 29 2721-2727. 

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... 

A few OP compounds cause delayed neuropathy in vertebrates because they inhibit another esterase located in the nervous system, which has been termed neuropathy target esterase (NTE). This enzyme is described in Chapter 10, Section 10.2.4. OPs that cause delayed neuropathy include diisopropyl phosphofluoridate (DFP), mipafox, leptophos, methamidophos, and triorthocresol phosphate. The delay in the appearance of neurotoxic symptoms following exposure is associated with the aging process. In most cases, nerve degeneration is not seen with initial inhibition of the esterase but appears some 2-3 weeks after commencement of exposure, as the inhibited enzyme undergoes aging (see Section 16.4.1). The condition is described as OP-induced delayed neuropathy (OPIDN). 

Hoffman, D.J., Sileo, L., and Murray, H.C. (1984). Subchronic OP induced delayed neurotoxicity in mallards. Toxicology and Applied Pharmacology 75, 128-136. 

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... 

The available inhalation data for Durad MP280, Fyrquel 220, Cellulube 220, Skydrol 500B-4, and cyclotriphosphazene (reviewed in the next paragraph) are inadequate to derive intermediate-duration MRLs for these individual fluids, principally because the studies were conducted in species (rats or rabbits) that are generally considered to be insensitive to the delayed neurotoxicity of acute exposure to organophosphate esters. Cats, dogs, or nonhuman primates more accurately model the human expression of OPIDN than rats and rabbits, and studies in these species would provide a better basis for MRL derivation. 

A third enzyme may have limited potential as a measure of exposure. Neurotoxic esterase, also known as neuropathy target esterase (NTE), is inhibited by certain organophosphate esters. When brain NTE is inhibited above 70% for acute or possibly as low as 50% for repeated exposures, there is a consensus that delayed neuropathy is likely. NTE also is found in lymphocytes and platelets (Lotti et al. 1984). The... 

Organophosphate Ester Hydraulic Fluids. Neurotoxicity is a concern from acute dermal, inhalation, or oral exposure to organophosphate ester hydraulic fluids because of the well-established susceptibility of humans to the cholinergic and delayed neuropathic properties of certain organophosphate ester compounds... 

---