Human Health Risk Assessment of Pesticide as Representative Xenobiotic

Protecting public health is the primary reason why risk assessment of xenobiotics, be they pharmaceuticals, agrochemicals, or industrial chemicals, is of utmost importance. Exposure to pesticides is a global challenge to risk assessment (Maroni et al. 2006).

Chronic exposure to low levels of pesticides can cause mutations and/ or carcinogenicity (Bull et al. 2006). On a worldwide basis, acute pesticide poisoning is an important cause of morbidity and mortality.

In an extrapolation, WHO/UNEP estimated that more than 3 million people were hospitalized for pesticide poisoning every year and that 220 000 died; it particularly noted that two-thirds of hospitalizations and the majority of deaths were attributable to intentional self-poisoning rather than to occupational or accidental poisoning.

Humans are inevitably exposed to pesticides in a variety of ways: at different dose levels and for varying periods of time (Boobiset al. 2008). This is why pesticides are used as representative xenobiotics in this research program.

General Considerations in Health Risk Assessment of Pesticides

In the health risk assessment of chemicals, the determination of a NOAEL (No Observed Adverse Effect Level) is often based on data only from animal experiments.

The safety or uncertainty factor 100 is used to convert NOAEL from an animal toxicity study to an ADI (Acceptable Daily Intake) value for human intake, ADI = NOAEL/100.

Historically, the assessment factor of 100 intended to cover the interspecies (animal-to-human) and inter-individual (human-to-human) variations has often been used as a default.

Based on factor 100, Renwick (Renwick 1991, Renwick 1993) has attempted to provide a scientific basis for the default values of 10 for interspecies and 10 for inter-individual variability.

Renwick also proposed a division of each of these factors into sub-factors to allow for separate evaluations of differences in toxicokinetic and toxicodynamic based on the relative magnitude of toxicokinetics and toxicodynamics variation between and within species.

He proposed that the 10-fold factors for inter- and intra-species variation should be subdivided into factors of 4 for toxicokinetics and 2.5 for toxicodynamics. WHO/IPCS has adapted the Renwick approach with one deviation.

While the uncertainty factor (UF) for interspecies extrapolation should be divided into default values of 4 for toxicokinetics and 2.5 toxicodynamics, the UF for inter-individual variation should be divided into 3.16- fold for both toxicokinetics and toxicodynamics.

The reason for this deviation from Renwick’s proposal was that the WHO/IPCS considered the slightly greater variability in the kinetics in humans compared with dynamics was not sufficient to warrant an unequal subdivision of the 10-fold factor into a toxicokinetic factor of 4 and a toxicodynamic factor of 2.5.

Toxic Effects of Pesticide Residues on Human Health

Many pesticides achieve their intended use of killing pests by disrupting the nervous system. Due to similarities in brain biochemistry among many different organisms, there is much assumption that these chemicals can have a negative impact on humans as well.

There are epidemiological studies that show positive correlations between exposures to pesticides through occupational hazard, which tends to be significantly higher than that ingested by the general population through food, and the occurrence of certain cancers (Damalas and Eleftherohorinos, 2011).

Although most of the general population may not expose to a large portion of pesticides, many of the pesticide residues that are attached tend to be lipophilic and can bio-accumulate in the body (Crinnionm, 2009)

Toxic effects of pesticides depend upon their toxicological properties, the level of residues and degree of exposure of human beings to residues. The presence of pesticide residues in grains does not necessarily mean that it is hazardous.

To be toxic, the residues have to be present in quantities large enough to be considered unsafe (Selvarajetal., 2014). The organophosphate, organochlorine and related pesticides act by binding to the enzyme acetylcholinesterase, disrupting nerve function, resulting in paralysis and may cause death.

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They may produce acute effects manifesting as meiosis, urination, diarrhea, diaphoresis, lacrimation, excitation of central nervous system and salivation. The chronic exposure involves neurotic and behavioral effects.

Specific effects of pesticides can include damage to the central and peripheral nervous systems, cancer, allergies and hypersensitivities, reproductive disorders and disruption of the immune system (Mishra etal,., 2014).

Neuronal damage due to cholinergic neuronal excite toxicity and dysfunction:

Following exposure to organophosphates, accumulation of acetylcholine at synapses results in rapid and profound excitotoxicity and dysfunction of cholinergic neurons in the brain.

Overstimulation of muscarinic acetylcholine receptors may also disrupt the balance of excitatory and inhibitory mechanisms to cause neuronal excitotoxic lesions leading to seizures and respiratory depression.

Seizures may result from over release of glutamate from glutamatergic neurons, triggering excessive calcium release in post-synaptic neuronal cells.

Seizures caused by cholinergic neuronal excitotoxic lesion in the brain may play a synergistic role in development of irreversible brain damage and long-term neurological and behavioural disorders.

Irreversible neural injury and neuronal cell death caused by organophosphate poisoning.

Serious neuropsychiatric impairments, including memory loss, inability to concentrate, speech problems, motor and sensory deficits, and behaviouralproblems.

In the first few hours after organophosphate poisoning, as the result of the cholinergic neuronal excitotoxicity, extensive intracellular edema, cerebral hemorrhages, intracellular calcium overload, oxidative stress and increased neuro inflammatory responses were generally observed in the affected brain regions.

The altered calcium influx activates lipases, proteases, kinases, phosphatases, and endonucleases in potentially harmful metabolic cascades, thus arresting protein synthesis and depriving cells of enzymes or trophic factors essential to their survival.

Many studies have demonstrated that obvious neuronal cell death, neural loss, and axonal degeneration were observed in different species of animals exposed to organophosphates.

Long-termneuro psychiatric and neurological disorders:

Exposure to organophosphates involve damage to cholinergic neurons of basal forebrain and the limbic system, which may cause memory, cognitive, mental, emotional, motor and sensory deficits by disrupting this putative sensory-limbic gating mechanism.

Persistent memory and cognitive deficits:

Memory and cognitive deficits are one of the most common and persistent behavioral sequelae in victims exposed to organophosphates.

Exposure to organophosphates sarin and cyclosarin at Khamisiyah resulted in long-term cognitive and memory impairments in the Gulf War-deployed veterans in 1991.

Chronic memory and cognitive impairments were also observed in the victims of the Tokyo subway sarin attack. 7 years after the Tokyo subway sarin attack, a chronic decline of memory function still existed in 23 subway workers exposed to sarin.

The exposed subway workers performed less well in the memory function tests, and their digit number of the backward digit span test was significantly smaller.

Loss of cholinergic neurons in the basal forebrain with aging results in a decline in cognitive capacity.

Psychomotor performance deficits and somatic complaints:

Clinical study has demonstrated that the Gulf War-deployed veterans exposed to sarin and cyclosarin at Khamisiyah suffered impaired fine psychomotor dexterity, reduced visuospatial abilities and deficits in motor function and coordination.

After the Tokyo subway sarin attack, a chronic decline of psychomotor function existed in 23 subway workers exposed to sarin for 7 years.

The high-exposure subway workers had a significantly slower performance of the finger tapping tests of both the dominant and non-dominant hands than control group.

In another clinical study, most of the victims of the Tokyo subway sarin attack were found to have long-lasting somatic complaints (such as gastrointestinal problems, constipation, heartburn, nausea, vomiting, colitis, migraines, headaches, backaches, and skin disorders) at 5 – 6 years after poisoning.

The long lasting somatic complaints and decreased psychomotor function of the victims exposed to organophosphates may be associated with neuronal damage in the cortex and thalamus.

Oxidative stress:

In sub chronic or chronic organophosphate exposition induction of oxidative stress has been reported as the main mechanism of organophosphate toxicity. Oxidative stress is induced in both acute and chronic intoxication with organophosphate compounds in humans and experimental animals.

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Hyperglycaemia is one of the mechanism of oxidative stress in organophosphate intoxication. Studies on chronic exposure to carbamate insecticides and case reports of long-term exposure give equivocal results.

An extensive survey of the toxicology of the common insecticide, carbaryl, reports a variety of reversible neurobehavioral and neurotoxic effects in vertebrates, all associated with acute poisoning symptoms.

The carbamate, carbofuran, has been observed to accentuate oxidative stress in rat brain by inducing lipid peroxidation and diminishing the antioxidant defense.

Development of cancer:

The studies on cancer analyze the risks associated with the consumption of specific products which have some pesticide residues. These consumption products include fish, water, seafood, and milk or other dairy products.

In general, these studies find a small but statistically significant association between cancer risks and some specific pesticide residues, such as dichlorodiphenyltrichloroethane and dichlorodiphenyltrichloroethane.

Specifically polychlorinated biphenyls present a higher risk for consumers. Organochlorine pesticide residue levelswere reported significantly higher in the cancer patients (Moon etal., 2009).

Reproductive disorders:

Results indicated that increase of insecticides in blood level in vertebrates causes reproductive dysfunction and suggested that for human beings food like fish, chick and goat containing beyond permissible limit of insecticides must be avoided.

Consumption of high pesticide residue fruits and vegetables was associated with lower total sperm count, ejaculate volume and percentage of morphologically normal sperm among men attending a fertility clinic (Chiu et al., 2015).

Pesticides exposure may lead to reduced fertility, early and late pregnancy loss, prolonged time-to-pregnancy, spontaneous abortion, and premature birth in female and genetic alterations in sperm, reduced sperm count, damage to germinal epithelium and altered hormone function in male.