Charles E. Becker

Organophosphate polyneuropathy Pathogenesis and prevention

Organophosphorus-induced delayed polyneuropathy (OPIDP) is initiated by the phosphorylation of a protein neurotoxic esterase (NTE) in the nervous system. A second step, the “aging” of the phosphoryl-enzyme complex, is required to produce the toxic effect. The experimental evidence for this molecular target and the importance of the aging process are reviewed. The catalytic activity of NTE has been used to develop an in vitro screening test that may distinguish the organophosphorus compounds (OPs) that cause neuropathy from those that do not, thereby providing a means for prevention of OPIDP. Moreover, a biochemical screening test, the determination of NTE activity in blood lymphocytes, may predict the development of OPIDP after acute or chronic exposure to OPs, and requires evaluation by carefully designed studies of occupational exposure to OPs.

HYDROXOCOBALAMIN AS A CYANIDE ANTIDOTE: SAFETY, EFFICACY AND PHARMACOKINETICS IN HEAVILY SMOKING NORMAL VOLUNTEERS

The safety, efficacy and pharmacokinetic parameters of 5 g of hydroxocobalamin given intravenously, alone or in combination with 12.5 g of sodium thiosulfate, were evaluated in healthy adult men who were heavy smokers. Sodium thiosulfate caused nausea, vomiting, and localized burning, muscle cramping, or twitching at the infusion site. Hydroxocobalamin was associated with a transient reddish discoloration of the skin, mucous membranes, and urine, and when administered alone produced mean elevations of 13.6% in systolic and 25.9% in diastolic blood pressure, with a concomitant 16.3% decrease in heart rate. No other clinically significant adverse effects were noted. Hydroxocobalamin alone decreased whole blood cyanide levels by 59% and increased urinary cyanide excretion. Pharmacokinetic parameters of hydroxocobalamin were best defined in the group who received both antidotes: t1/2 (alpha), 0.52 h; t1/2 (beta), 2.83 h; Vd (beta), 0.24 L/kg; and mean peak serum concentration 753 mcg/mL (560 mumol/L) at 0-50 minutes after completion of infusion. Hydroxocobalamin is safe when administered in a 5 gram intravenous dose, and effectively decreases the low whole blood cyanide levels found in heavy smokers.

Serum Formate Concentrations in Methanol Intoxication as a Criterion for Hemodialysis

To evaluate the utility of serum formate concentrations, four patients were studied after ingestion of a methanolic copying fluid. All patients were initially intoxicated. Twelve to twenty-four hours later, signs and symptoms included nausea, abdominal pain, hypokalemia, acidosis (three patients), and pathologic ocular findings (two patients). All patients were treated with ethanol and folate. The two patients with ocular signs and acidosis had high serum formate concentrations (75 and 55 mg/dL, respectively). One of the two patients had a high methanol concentration (222 mg/dL) and required hemodialysis; the other patient did not (methanol concentration, 24 mg/dL). In the other two patients without ocular signs, initial formate concentrations were undetectable (limit of detection, 0.5 mg/dL); however, one patient required hemodialysis because the methanol concentration was 72 mg/dL. Formate is the mediator of ocular injury and acidosis. In these patients formate concentrations correlated with the clinical condition but methanol concentrations did not.

Occupational Infection with Human Immunodeficiency Virus (HIV): Risks and Risk Reduction

As the epidemic of the acquired immunodeficiency syndrome (AIDS) expands, the prevalence of the human immunodeficiency virus (HIV) infection in health care environments will increase and health care workers in many locations are likely to be at increased risk for exposure. The Fifth Annual Advances in Occupational Cancer Conference, held in December 1988 in San Francisco, addressed occupational HIV infection. Symposium participants concluded that the risk of HIV infection for health care workers is low but not zero. Implementation of universal blood and body fluid precautions was agreed to as an appropriate method of preventing exposure to HIV, especially for preventing needlestick accidents. Current standards for hospital waste disposal were judged to be adequate to prevent transmission of HIV, and confidential testing for HIV antibody in health care workers with follow-up counseling was recommended where indicated. It was also agreed that the risk of occupational exposure to HIV does not free health care workers from the responsibility to provide care to infected persons.

Potential Pitfalls in the Evaluation of the Usefulness of Hemodialysis for the Removal of Lithium

A 50-year old female who was comatose from an overdose of lithium was treated with hemodialysis. Serum lithium concentrations declined 47% during a 3-h hemodialysis but increased afterwards, peaking 8 h after hemodialysis was stopped. Hemodialysis clearances were estimated by equations using extraction ratios of lithium from whole blood, serum, and red cells, and flows of whole blood, serum or red cells. The amount of lithium removed was calculated from these clearances as well as measured directly in the dialysate. Errors were introduced into the calculation of the amount of lithium removed by hemodialysis unless whole blood concentrations of lithium and whole blood flows were used. These arose because extraction of lithium from serum (0.7 +/- 0.3, mean +/- SD) was greater than that from whole blood (0.49 +/- 0.06) or from red blood cells (0.18 +/- 0.12). Despite the rapid decrease in serum concentrations of lithium during hemodialysis and rebound afterwards, the patients neurologic status did not change concurrently. The patient did not regain consciousness until lithium concentrations fell to less than 0.4 meq/L in serum and 0.1 meq/L in cerebrospinal fluid. The lack of parallel change in serum concentrations and coma probably reflects the lag time in equilibration between lithium concentrations in serum and brain.

Passive Absorption of Nicotine in Airline Flight Attendants

To the Editor: There is concern that nonsmokers may suffer adverse health effects from exposure to side-stream cigarette smoke (March 27, 1980, issue).1 Airline flight attendants are regularly expo...

Coma, Hyperthermia, and Bleeding Associated with Massive LSD Overdose a Report of Eight Cases

Eight patients were seen within 15 min of intranasal self-administration of large amounts of pure D-lysergic acid diethylamide (LSD) tartrate powder. Emesis and collapse occurred along with sign of sympathetic overactivity, hyperthermia, coma, and respiratory arrest. Mild generalized bleeding occurred in several patients and evidence of platelet dysfunction was present in all. Serum and gastric concentrations of LSD tartrate ranged from 2.1 to 26 ng/ml and 1000 to 7000 mug/100 ml, respectively. With supportive care, all patients recovered. Massive LSD overdose in humans is life-threatening and produces striking and distinctive manifestations.

Cross-sectional neurotoxicology study of lead-exposed cohort

Although the toxic effects of lead have been known for centuries, lead intoxication is still widespread in the United States. Without baseline tests of neuropsychological, neurobehavioral and neurophysiological testing it may be difficult to detect subtle changes in neurological function after lead exposure. This may be further confounded by partial chelation treatment and exposure to neurotoxic mixtures or inability to quantitate alcohol consumption. We undertook a cross-sectional study to address these problems in 24 exposed and 29 control subjects in a plant that manufactured electrical components using fritted leaded glass to coat capacitors and transistors. Potentially exposed workers had blood lead levels ranging between 3 micrograms/dL to 135 micrograms/dL. Industrial hygiene monitoring revealed the plants air lead levels ranged from 61 micrograms/m3 to 1,700 micrograms/m3 in excess of OSHA permissible exposure limits of 40 micrograms/m3/10 hr day. Using a specially designed battery of neurophysiological, neurobehavioral and neuropsychological screening tests, we demonstrated a significant difference from controls in measures of psychomotor speed, motor strength and verbal memory. Although limited by the cross-sectional design, these findings support the hypothesis that the battery of neurophysiological, neuropsychological and neurobehavioral tests can detect a significant inter-group differences between lead-exposed and control subjects.

Environmental lead exposure and the kidney.

Lead and its components remain widely distributed in the environment and in some workplaces. Lead serves no useful physiological function, yet is potentially toxic to several organ systems. For many years human health effects have been recognized after heavy lead exposure. Recently more subtle human effects have been suggested invoking nervous system, reproductive and kidney function. Assessing lead body burden and dose-response relationships of this metal by blood lead determination, porphyrin assessments, chelation testing or bone lead studies may be difficult. Quantitative assessment of subtle changes in kidney function by routine BUN, creatinine, or urinalysis also poses problems. There is now mounting evidence that chronic low level environmental lead exposure may subtly effect kidney function. This paper first examines the history of lead and kidney function and then examines critically the evidence associating low-level environmental lead exposure and effects on renal function.

Use of cathartics in toxic ingestions

Cathartics are commonly recommended for treatment of ingestion of toxic substances. Literature review shows little evidence of efficacy of this practice. Published reports of morbidity are limited to pediatric patients experiencing electrolyte imbalance. Our survey of the members of the American Board of Toxicology, as well as our literature review, form the basis for suggesting catharsis of most patients when treating toxic ingestions. However, caution must be used in very old or very young patients, in those with preexisting renal disease or ingestion of nephrotoxic substances, in corrosive ingestions, in patients with recent bowel surgery or absent bowel sounds, and in patients with hypertension or congestive heart failure. Oil catharsis is not recommended.