Elsevier

Toxicology

Volumes 181–182, 27 December 2002, Pages 23-33
Toxicology

Low level exposures to organophosphorus esters may cause neurotoxicity

https://doi.org/10.1016/S0300-483X(02)00447-XGet rights and content

Abstract

A large number of published studies support the notion that long term, low level (LTLL) exposure to organophosphorus (OP) esters may cause neurological and neurobehavioral effects. In order to differentiate these from other effects of OP such as the acute cholinergic episodes, intermediate syndrome and organophosphate induced delayed neuropathy (OPIDN), the term Chronic Organophosphate Induced Neuropsychiatric Disorder (COPIND) will be used purely for the ease of reference. The question addressed in this particular review is whether LTLL exposure to OP may produce neurotoxicity. The profile and the degree of overlap of the various components of COPIND have been addressed elsewhere and description of the possible mechanisms for COPIND is outside the scope of this article. COPIND can be classified under two headings; those produced following one or more acute clinical cholinergic episodes, and those produced without such preceding attacks. With regards to the first group, there are a total of 11 studies, all of which support the existence of a positive link between exposure to OP and neurotoxicity; six of these studies comprise descriptions of large numbers of cases without controls while five additional studies employ controls. Appearance of neurotoxicity does not seem to be related to the number or the intensity of acute cholinergic attacks. With regards to the second group, three types of studies can be identified. Firstly, there are five studies using experimental animals, all of which showed a positive link between OP and neurotoxicity. Secondly, a total of seven case studies without controls, some involving large numbers of patients, concluded that there is a positive link between OP and neurotoxicity. Thirdly, 19 studies investigated such a link using cases and control groups. Of these, 15 studies (about 80%) showed a positive link and only four failed to identify any link between OP and neurotoxicity. Annotation of all the 19 studies according to ideal set of criteria showed that only a few of these comply with the rules of excellence and all of these few showed a positive link. Furthermore, the only study carried out blind without the identification of subjects or controls, showed a positive link between OP and neurotoxicity. This blind study estimated the overall incidence of a form of neurotoxicity in people exposed to OP to be about 40 times higher than in the general population. The type of neurological involvement was unique and different from OP induced syndromes previously described. The profile of the neurological involvement was similar to that in COPIND whether or not preceded by acute cholinergic episodes, thus providing further evidence that these two neuropathies probably share a similar mechanism. There is a characteristic pattern of involvement of 15 functional indices of the autonomic nervous system examined in our laboratory. There are, in addition, preferential anatomical sites of target organs affected, selective preservation of cholinergic function within the same neuropathy-positive site, and evidence of mal-function of cardiac chemoreceptors in patients exposed to OP. The peripheral nerve involvement in OP exposure is predominantly sensory in nature affecting both small and large fibre populations. Neurobehavioral involvement of mainly cognitive dysfunction and other features are also described in other studies. The weight of current evidence is therefore very much in favor of the motion that chronic low-level exposure to OP produces neurotoxicity. Criticisms levelled against this motion are unfounded and probably misconceived.

Introduction

Exposure to organophosphorus (OP) esters can cause several syndromes including acute cholinergic clinical episodes, the so-called Intermediate syndrome, organophosphate induced delayed neuropathy (OPIDN) and chronic neurological effects. Acute toxicity is produced by irreversible inactivation of the enzyme cholinesterases, the exact mechanism of the intermediate syndrome is not understood while the OPIDN is claimed to be ‘marked’ by the inhibition and subsequent ageing (dealkylation) of a protein enzyme in nerve cells called neuropathy target esterase (NTE). The ability to produce OPIDN is not even related to the degree of inhibition of AchE and there is no indication that the intermediate syndrome is related to the cholinergic effect of OP compounds. It took the medical and scientific body more than 50 years to recognise OPIDN despite its dramatic nature of clinical presentation.

Chronic neurological effects have been reported to occur either following one or more attacks of acute cholinergic episodes or following long-term, low-level (LTLL) exposure to OP compounds. In order to differentiate the chronic neurological effects from the rest of the OP syndromes, the term Chronic Organophosphate Induced Neuropsychiatric Disorder (COPIND) is used for ease of reference. The remit of this review is confined to providing affirmative evidence to the title statement that low-level exposure to OP esters may cause neurotoxicity. It is not the remit of this article to describe the profile of the chronic toxicity or to discuss the possible underlying mechanisms of such chronic toxicity. These have been described elsewhere (Jamal, 1997) but will be mentioned briefly, given the limited space.

Section snippets

Review of studies in the literature

Studies concerning the chronic effects of OP esters are discussed in this review under two different headings; studies of COPIND following one or more acute clinical cholinergic episodes and COPIND without preceding cholinergic attacks.

Conclusion

  • Each and every study available in the literature concludes that chronic neurotoxicity can follow one or more acute clinical cholinergic episodes. The development of chronic neurotoxicity seems to be unrelated to the number or the severity of the acute cholinergic attacks.

  • With regards to the relationship between long term low level exposure to OP (with no history of preceding acute cholinergic episodes) and development of chronic neurotoxicity, the following conclusions can be made: All studies

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