TR 075 : Organophosphorus Pesticides and Long-term Effects on the Nervous System | December 1998
Organophosphorus pesticides (OPps) have been used for decades. In view of their potent biological effects, these agents are subject to toxicological scrutiny aimed at the recognition of potential hazards and their risk management. In addition to the “classical” hazards of acute toxicity and delayed neuropathy, termed organophosphorus-induced delayed neuropathy (OPIDN), other specific types of organophosphorus neurotoxicity, such as “intermediate syndrome”, ocular “Saku disease” and more recently “chronic syndrome” have been allegedly associated with OPp exposure. It has been claimed that even low-level, apparently asymptomatic chronic exposure could cause long-term adverse effects on the nervous system. This prompted ECETOC to review the existing epidemiological data and toxicological testing protocols for the development and registration of OPps, with respect to their sensitivity and reliability for detecting such effects.
The present report reviews studies relating to long-term effects in humans, discriminating between chronic effects of acute or repeated exposure strong enough to produce clinical signs and symptoms (symptomatic exposure) and the effects of chronic, low-level, apparently asymptomatic exposure. These two fundamentally different situations are often confused in the literature. In addition, chronic, low-level exposure may have been associated in some studies with undocumented episodes of acute intoxication and the signs, symptoms and sequelae of acute exposure mistakenly interpreted as effects of chronic exposure. Some epidemiological studies demonstrate the absence of adverse effects in cohorts exposed but protected (by protective clothing) and thus confirm the possibility of using OPps safely. Others report adverse effects that vary but are predominantly either psychological, neurological or ophthalmological. Unfortunately, both the “positive” and the “negative” epidemiological studies often lack sufficient details of the conditions, levels of exposure and compounds involved and data are frequently confounded by the spontaneous occurrence of changes related to aging and underlying diseases. Moreover, most studies are retrospective and methods of examination have not been standardised, are frequently subjective and rarely appropriately controlled. Therefore, at present, the evidence for the alleged chronic effects arising from low-level exposure appears insufficient. In most studies, there are no specific complaints about oculotoxicity resulting from chronic exposure. This is of interest in that oculotoxicity was previously suspected and special animal tests for this effect were required.
This report also reviews experimental and mechanistic studies focused on chronic OPp effects. It concludes that animal experiments, aimed at further characterising neurotoxicity induced by specific OPps, confirm acute and protracted effects on cognitive functions but have not demonstrated the alleged effects of prolonged, low-level exposure. Kinetic data demonstrate that inhibition of cholinesterase (ChE) by multiple low doses increases only during the initial phase of exposure and thereafter reaches a steady state, so that there is no long-range cumulative inhibition. No convincing explanation of how chronic, low-level exposure could possibly culminate in chronic dysfunction has been provided. Several mechanisms have been proposed, such as changes in receptors or neurotransmission, potential non-cholinergic effects of ChE or of OPps, or inhibition of other proteins/enzymes. However, in the absence of a demonstration that such effects really do occur at doses too small to cause acute or sub-acute effects, these hypotheses cannot be used as a foundation for the understanding of OPp neurotoxicity.
The testing protocols used in animal safety studies have been reviewed with respect to their ability to identify OPp effects. The effects known or alleged to occur in humans have been compared to the toxicological “end-points” observed in animals. This comparison has demonstrated good predictability of the acute and delayed neuropathic effects. Although some chronic effects can be predicted from animal studies, there are restrictions caused by the short natural lifespan of experimental animals and by the restricted capability of animal experiments to test for exclusively-human mental performance.
For the sake of completeness and to facilitate the comprehensive understanding of OPp toxicology, an Appendix to the report has been provided, with reviews of experimental and clinical data related to acute effects, intermediate syndrome, and OPIDN.
The Task Force has arrived at the following conclusions:
Acute and intermediate effects
The primary neurotoxic effects of OPps on humans and animals are well understood. Such effects are generally reversible. Nevertheless, acute poisoning due to severe overdose can produce persistent changes. The acute toxicity of OPps is appropriately assessed in regulatory animal safety studies, well documented in humans, and clinically manageable. The intermediate syndrome is always associated with prior acute effects and the number of reported cases is limited. Risk from such hazards can be managed by minimising exposure.
Neuropathic effects (OPIDN)
The potential to induce OPIDN can be reliably detected by monitoring neuropathy target esterase (NTE) inhibition and by adequate neuropathological examination in delayed neurotoxicity studies in hens. It is unlikely that chronic, low-level inhibition of NTE could cause neuropathy, because OPIDN is a threshold event. In any case such effects would have been observed in sub-chronic and chronic safety studies in rats and dogs had they occurred. Most cases of OPIDN have been caused by non-pesticidal organophosphorus compounds such as triorthocresyl phosphate (TOCP).
There is no pharmacokinetic evidence for cumulative effects of chronic exposures to OPps at levels which are not acutely toxic. With prolonged substantial exposure the sensitivity to OPps decreases owing to the development of tolerance, and the effects are reversible after cessation of exposure. Based on well-established pharmacological and toxicokinetic principles, irreversible sequelae of low-level exposure are considered unlikely. Tolerability studies in human volunteers conducted with a number of specific OPps indicate the absence of sequelae from daily, low-level asymptomatic exposure lasting for several weeks.
There is insufficient evidence in the epidemiological literature that there is a “chronic syndrome” resulting form chronic, apparently asymptomatic exposure. To resolve the question of whether or not such a syndrome does exist, surveillance of the exposed populations is considered more appropriate than additional animal studies. The described features of “chronic syndrome” resemble the complaints and changes sometimes seen in the general population and known to be linked to other societal and socio-economic factors. Interpretation of epidemiological observations should take such confounding factors into consideration.
Some of the toxic effects claimed to constitute the alleged “chronic syndrome” can be detected in general regulatory safety studies and in special neurotoxicity studies within the constraints of interspecies extrapolation. There are human mental capabilities which are not testable in animals. Therefore, and in the absence of hard evidence of the key features of ‘chronic syndrome’ in humans with low-level, asymptomatic exposure, it is not feasible to propose modifications of present regulatory animal studies.
Review of reported complaints indicates that oculotoxicity does not appear to be a hazard of chronic OPp exposure. Persistent ocular effects are not observed in most epidemiological studies. In animal studies, ophthalmoscopy and biomicroscopy, supported by adequate pathology examination, provide sufficient sensitivity for detecting adverse effects in standard animal regulatory safety studies.
Based on the current state of the science, the Task Force has concluded that the evidence for “chronic syndrome” is insufficient, but recommends that the epidemiology studies currently planned are followed up and the issue re-visited when results are available.