Neurologic Effects

The adult nervous system is a critical target for the toxic effects of lead. Effects on the central nervous system of lead workers include dose-related changes in cognitive and psychomotor performance and mood, neurodegenera-tive diseases, and neurophysiologic changes in the auditory, visual, and balance systems. Effects of occupational lead exposure on the peripheral nervous system at BLLs of 60-70 pg/dL are manifested as motor weakness with abnormahties in motor and sensory nerve conduction. No peripheral motor or sensory symptoms are known to occur at BLLs imder 40 pg/dL, but sensory nerve function is associated with lead dose. 

Potential modes of action for lead neurotoxicity include oxidative stress, inhibition of enzymes needed for energy production, decreased levels of neurotransmitters and altered neurotransmitter release, and increased permeability of the blood-brain barrier (EPA 2012). Ultimately, lead-induced neurotoxicity in adults consists of changes in brain stracture and neurochemistry, including white-matter changes, reduction in gray matter, and alterations in brain metabolites. 

Conclusions from the Environmental Protection Agency 2006 and 2012 and National Toxicology Program 2012 Lead Documents 

Environmental Protection Agency 2006 Air Quality Criteria Document 

EPA s 2012 Integrated Science Assessment for Lead (Second External Review Draft) focused on updating the 2006 Air Quality Criteria Document for Lead (EPA 2006), so a smmnary of the key neurotoxic effects of lead in adults from the earlier document will be presented first. 

---

Lowest observed effect level (PbB) (Mg/dl) Heme synthesis and hematological effects Neurological effects Renal system effects Gastrointestinal effects ... 

Very few data are available on the effects of organotins in humans. Of the reported unintentional occupational exposures, none has an estimate of exposure concentration. Exposure was largely via the inhalation route, with some possibility of dermal exposure. Neurological effects were the most commonly reported, and these can persist for long periods. 

Neurological effects related to cholinesterase depression occurred in seven children acutely exposed to methyl parathion by inhalation as well as orally and dermally (Dean et al. 1984). The children were admitted to a local hospital with signs and symptoms of lethargy, increased salivation, increased respiratory secretions, and miosis. Two of the children were in respiratory arrest. Two children died within several days of each other. All of the children had depressed plasma and erythrocyte cholinesterase levels (Table 3-2). These effects are similar to those occurring in methyl parathion intoxication by other routes (see Sections 3.2.2.4 and 3.2.3.4). Three adults exposed in the same incident had normal plasma (apart from one female) and red blood cell cholinesterase, and urinary levels of 4-nitrophenol (0.46-12.7 ppm) as high as some of the ill children. 

Reductions in erythrocyte and plasma cholinesterase levels are considered biomarkers of neurological effects and not hematological effects as discussed in Sections 3.2.2.4 and 3.5.2. 

Respiratory Effects. Pulmonary edema has been reported in humans who died of acute methyl parathion (Wofatox) intoxication (Fazekas 1971). Edema was foimd in a man who died 2 horn s after intoxication and in others who died as long as 9 days after exposure. Bronchoconstriction and h er-secretion of bronchial glands are primary muscarinic effects of methyl parathion. Pulmonary edema is not considered to be a primary effect of methyl parathion it is considered to be secondary to the neurologic effects of this compound on the heart and vascular smooth muscle. 

Renal Effects. Acute nephrosis has been reported in humans after acute, lethal intoxication (Fazekas 1971) by methyl parathion (Wofatox). This may be a secondary effect of hypoxia related to the neurologic effects of methyl parathion on vascular smooth muscle and on the electrical conduction system of the heart. It could also be related to therapeutic efforts. 

Neurological effects related to cholinesterase depression occurred in seven children acutely exposed to methyl parathion by inhalation as well as orally and dermally (Dean et al. 1984). See Section 3.2.1.4 for additional details. 

All reliable LOAEL values for neurological effects in rats for the acute-duration category, the highest NOAEL and all reliable LOAEL values in dogs for the intermediate-duration category, and the highest... 

In the male offspring whose treatment was continued through 11-12 weeks of age, however, dose-related effects were seen on all the above end points, and these effects were significantly different from controls at all three dose levels (Desi et al. 1998) (see also Section S.2.2.4). The study did not determine the critical period (if any) and duration of exposure for these neurological effects. A limitation of this study is that results specifically for methyl parathion were shown only for the somatosensory electrocortico-gram the other results for this chemical were stated in the text, but not shown. 

Following exposure of humans to organophosphates, but not specifically methyl parathion, restoration of plasma cholinesterase occurs more rapidly than does restoration of erythrocyte cholinesterase (Grob et al. 1950 Midtling et al. 1985). These findings are supported by studies of methyl parathion in animals. Erythrocyte cholinesterase levels are representative of acetylcholinesterase levels in the nervous system, and, therefore, may be a more accurate biomarker of the neurological effects of chronic low level exposure of humans to methyl parathion (Midtling et al. 1985 NIOSH 1976). 

Other additional studies or pertinent information that lend sunnort to this MRL Methyl parathion affects the nervous system by inhibiting acetylcholinesterase activity. Cholinesterase inhibition and neurological effects have been observed in humans and animals, for all exposure routes and durations (for example. Dean et al. 1984 Desi et al. 1998 EPA 1978e Gupta et al. 1985 Nemec et al. 1968 Suba 1984). 

Similarly, convulsive seizures and a sustained epileptic state persisted after stomach contents were pumped and activated charcoal and anticonvulsive medication were administered in a 43-year-old man who ingested approximately 260 mg/kg endosulfan (Boereboom et al. 1998). At 4 days after exposure, the man was pronounced brain dead, and autopsy revealed cerebral hernia from massive cerebral edema. Eight additional accidental and/or intentional cases of acute poisoning with endosulfan resulting in adverse neurological effects have been reported in more recent studies, six by Blanco-Coronado et al. (1992), one by Lo et al. (1995), and one by Pradhan et al. (1997) two out of the eight resulted in death. Tonic-clonic convulsions were seen in the Blanco-Coronado et al. (1992) cases, whereas Lo et al. (1995) reported the development of muscle fasciculations and episodes of convulsions in their case. In the case reported by Pradhan et al. (1997), the patient had consumed about 75 mL of hquid endosulfan (35% w/v). In this case, in addition to tonic-clonic seizures and myoclonic jerks, the patient developed... 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and duration category are recorded in Table 2-2 and plotted in Eigure 2-2. In some studies, only the a- or The -isomer of endosulfan was tested. In such cases, a notation regarding the specific isomer tested is included in the effect description. 

Indirect evidence indicates that dermal absorption occurs in animals. Calves dusted with a 4% dust formulation of endosulfan had neurological symptoms (tremors, twitching, convulsions) and died within a day after exposure (Nicholson and Cooper 1977). Neurological effects have also been reported in preclipped rabbits and rats after repeated application of endosulfan to the skin (Dikshith et al. 1988 Gupta and Chandra 1975). Dikshith et al. (1988) reported levels of a-, [3-, and total endosulfan in liver, kidney, brain, testes, fatty tissue, and blood 30 days after dermal application of endosulfan. 

---