Showing papers in "Toxicological Reviews in 2003"

The role of oximes in the management of organophosphorus pesticide poisoning

Abstract: The number of intoxications with organophosphorus pesticides (OPs) is estimated at some 3,000,000 per year, and the number of deaths and casualties some 300,000 per year. OPs act primarily by inhibiting acetylcholinesterase (AChE), thereby allowing acetylcholine to accumulate at cholinergic synapses, disturbing transmission at parasympathetic nerve endings, sympathetic ganglia, neuromuscular endplates and certain CNS regions. Atropine is the mainstay of treatment of effects mediated by muscarine sensitive receptors; however, atropine is ineffective at the nicotine sensitive synapses. At both receptor types, reactivation of inhibited AChE may improve the clinical picture. The value of oximes, however, is still a matter of controversy. Enthusiastic reports of outstanding antidotal effectiveness, substantiated by laboratory findings of reactivated AChE and improved neuromuscular transmission, contrast with many reports of disappointing results. In vitro studies with human erythrocyte AChE, which is derived from the same single gene as synaptic AChE, revealed marked differences in the potency and efficacy of pralidoxime, obidoxime, HI 6 and HLo 7, the latter two oximes being considered particularly effective in nerve agent poisoning. Moreover, remarkable species differences in the susceptibility to oximes were revealed, requiring caution when animal data are extrapolated to humans. These studies impressively demonstrated that any generalisation regarding an effective oxime concentration is inappropriate. Hence, the 4 mg/L concept should be dismissed. To antagonise the toxic effects of the most frequently used OPs, pralidoxime plasma concentrations of around 80 mumol/L (13.8 mg/L pralidoxime chloride) should be attained while obidoxime plasma concentrations of 10 mumol/L (3.6 mg/L obidoxime chloride) may be sufficient. These concentrations should be maintained as long as circulating poison is expected to be present, which may require oxime therapy for up to 10 days. Various dosage regimens exist to reach this goal. The most appropriate consists of a bolus short infusion followed by a maintenance dosage. For pralidoxime chloride, a 1 g bolus over 30 minutes followed by an infusion of 0.5 g/h appears appropriate to maintain the target concentrtion of about 13 mg/L (70 kg person). For obidoxime chloride, the appropriate dosage is a 0.25 g bolus followed by an infusion of 0.75 g/24 h. These concentrations are well tolerated and keep a good portion of AChE in the active state, thereby retarding the AChE aging rate. AChE aging is particularly rapid with dimethyl phosphoryl compounds and may thwart the effective reactivation by oximes, particularly in suicidal poisoning with excessive doses. In contrast, patients with diethyl OP poisoning may particularly benefit from oxime therapy, even if no improvement is seen during the first days when the poison load is high. The low propensity to aging with diethyl OP poisoning may allow reactivation after several days, when the poison concentration drops. Rigorous testing of the benefits of oximes is only possible in randomised controlled trials with clear stratification according to the class of pesticides involved, time elapsed between exposure and treatment and severity of cholinergic symptoms on admission.

Health Implications of Exposure to Environmental Nitrogenous Compounds

Abstract: All living systems need nitrogen for the production of complex organic molecules, such as proteins, nucleic acids, vitamins, hormones and enzymes. Due to the intense use of synthetic nitrogen fertilisers and livestock manure in modern day agriculture, food (particularly vegetables) and drinking water may contain higher concentrations of nitrate than in the past. The mean intake of nitrate per person in Europe is about 50–140 mg/ day and in the US about 40–100 mg/day. In the proximal small intestine, nitrate is rapidly and almost completely absorbed (bioavailability at least 92%). In humans, approximately, 25% of the nitrate ingested is secreted in saliva, where some 20% (about 5–8% of the nitrate intake) is converted to nitrite by commensal bacteria. The nitrite so formed is then absorbed primarily in the small intestine. Nitrate may also be synthesised endogenously from nitric oxide (especially in case of inflammation), which reacts to form nitrite. Normal healthy adults excrete in the urine approximately 62mg nitrate ion/day from endogenous synthesis. Thus, when nitrate intake is low and there are no additional exogenous sources (e.g. gastrointestinal infections), the endogenous production of nitrate is more important than exogenous sources. Nitrate itself is generally regarded nontoxic. Toxicity is usually the result of the conversion of nitrate into the more toxic nitrite. There are two major toxicological concerns regarding nitrite. First, nitrite may induce methaemoglobinaemia, which can result in tissue hypoxia, and possibly death. Secondly, nitrite may interact with secondary or N-alkyl-amides to form N-nitroso carcinogens. However, epidemiological investigations and human toxicological studies have not shown an unequivocal relationship between nitrate intake and the risk of cancer. The Joint Expert Committee of the Food and Agriculture Organization of the United Nations/World Health Organization (JECFA) and the European Commission’s Scientific Committee on Food have set an acceptable daily intake (ADI) for nitrate of 0–3.7mg nitrate ion/kg bodyweight; this appears to be safe for healthy neonates, children and adults. The same is also true of the US Environmental Protection Agency (EPA) Reference Dose (RfD) for nitrate of 1.6mg nitrate nitrogen/kg bodyweight per day (equivalent to about 7.0mg nitrate ion/kg bodyweight per day). This opinion is supported by a recent human volunteer study in which a single dose of nitrite, equivalent to 15–20 times the ADI for nitrate, led to only mild methaemoglobinaemia (up to 12.2%), without other serious adverse effects. The JECFA has proposed an ADI for nitrite of 0–0.07mg nitrite ion/kg bodyweight and the EPA has set an RfD of 0.1mg nitrite nitrogen/kg bodyweight per day (equivalent to 0.33mg nitrite ion/kg bodyweight per day). These values are again supported by human volunteer studies.

Ricin. Mechanisms of cytotoxicity.

Abstract: Ricin is a heterodimeric protein produced in the seeds of the castor oil plant (Ricinus communis). It is exquisitely potent to mammalian cells, being able to fatally disrupt protein synthesis by attacking the Achilles heel of the ribosome. For this enzyme to reach its substrate, it must not only negotiate the endomembrane system but it must also cross an internal membrane and avoid complete degradation without compromising its activity in any way. Cell entry by ricin involves a series of steps: (i) binding, via the ricin B chain (RTB), to a range of cell surface glycolipids or glycoproteins having beta-1,4-linked galactose residues; (ii) uptake into the cell by endocytosis; (iii) entry of the toxin into early endosomes; (iv) transfer, by vesicular transport, of ricin from early endosomes to the trans-Golgi network; (v) retrograde vesicular transport through the Golgi complex to reach the endoplasmic reticulum; (vi) reduction of the disulphide bond connecting the ricin A chain (RTA) and the RTB; (vii) partial unfolding of the RTA to render it translocationally-competent to cross the endoplasmic reticulum (ER) membrane via the Sec61p translocon in a manner similar to that followed by misfolded ER proteins that, once recognised, are targeted to the ER-associated protein degradation (ERAD) machinery; (viii) avoiding, at least in part, ubiquitination that would lead to rapid degradation by cytosolic proteasomes immediately after membrane translocation when it is still partially unfolded; (ix) refolding into its protease-resistant, biologically active conformation; and (x) interaction with the ribosome to catalyse the depurination reaction. It is clear that ricin can take advantage of many target cell molecules, pathways and processes. It has been reported that a single molecule of ricin reaching the cytosol can kill that cell as a consequence of protein synthesis inhibition. The ready availability of ricin, coupled to its extreme potency when administered intravenously or if inhaled, has identified this protein toxin as a potential biological warfare agent. Therapeutically, its cytotoxicity has encouraged the use of ricin in 'magic bullets' to specifically target and destroy cancer cells, and the unusual intracellular trafficking properties of ricin potentially permit its development as a vaccine vector. Combining our understanding of the ricin structure with ways to cripple its unwanted properties (its enzymatic activity and promotion of vascular leak whilst retaining protein stability and important immunodominant epitopes), will also be crucial in the development of a long awaited protective vaccine against this toxin. Language: en

Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue.

Abstract: Methaemoglobin is formed by oxidation of ferrous (FeII) haem to the ferric (FeIII) state and the mechanisms by which this occurs are complex. Most cases are due to one of three processes. Firstly, direct oxidation of ferrohaemoglobin, which involves the transfer of electrons from ferrous haem to the oxidising compound. This mechanism proceeds most readily in the absence of oxygen. Secondly, indirect oxidation, a process of co-oxidation which requires haemoglobin-bound oxygen and is involved, for example, in nitrite-induced methaemoglobinaemia. Thirdly, biotransformation of a chemical to an active intermediate that initiates methaemoglobin formation by a variety of mechanisms. This is the means by which most aromatic compounds, such as amino- and nitro-derivatives of benzene, produce methaemoglobin. Methaemoglobinaemia is an uncommon occupational occurrence. Aromatic compounds are responsible for most cases, their lipophilic nature and volatility facilitating absorption during dermal and inhalational exposure, the principal routes implicated in the workplace. Methaemoglobinaemia presents clinically with symptoms and signs of tissue hypoxia. Concentrations around 80% are life-threatening. Features of toxicity may develop over hours or even days when exposure, whether by inhalation or repeated skin contact, is to relatively low concentrations of inducing chemical(s). Not all features observed in patients with methaemoglobinaemia are due to methaemoglobin formation. For example, the intravascular haemolysis caused by oxidising chemicals such as chlorates poses more risk to life than the methaemoglobinaemia that such chemicals induce. If an occupational history is taken, the diagnosis of methaemoglobinaemia should be relatively straightforward. In addition, two clinical observations may help: firstly, the victim is often less unwell than one would expect from the severity of 'cyanosis' and, secondly, the 'cyanosis' is unresponsive to oxygen therapy. Pulse oximetry is unreliable in the presence of methaemoglobinaemia. Arterial blood gas analysis is mandatory in severe poisoning and reveals normal partial pressures of oxygen (pO2) and carbon dioxide (pCO2,), a normal 'calculated' haemoglobin oxygen saturation, an increased methaemoglobin concentration and possibly a metabolic acidosis. Following decontamination, high-flow oxygen should be given to maximise oxygen carriage by remaining ferrous haem. No controlled trial of the efficacy of methylene blue has been performed but clinical experience suggests that methylene blue can increase the rate of methaemoglobin conversion to haemoglobin some 6-fold. Patients with features and/or methaemoglobin concentrations of 30-50%, should be administered methylene blue 1-2 mg/kg/bodyweight intravenously (the dose depending on the severity of the features), whereas those with methaemoglobin concentrations exceeding 50% should be given methylene blue 2 mg/kg intravenously. Symptomatic improvement usually occurs within 30 minutes and a second dose of methylene blue will be required in only very severe cases or if there is evidence of ongoing methaemoglobin formation. Methylene blue is less effective or ineffective in the presence of glucose-6-phosphate dehydrogenase deficiency since its antidotal action is dependent on nicotinamide-adenine dinucleotide phosphate (NADP+). In addition, methylene blue is most effective in intact erythrocytes; efficacy is reduced in the presence of haemolysis. Moreover, in the presence of haemolysis, high dose methylene blue (20-30 mg/kg) can itself initiate methaemoglobin formation. Supplemental antioxidants such as ascorbic acid (vitamin C), N-acetylcysteine and tocopherol (vitamin E) have been used as adjuvants or alternatives to methylene blue with no confirmed benefit. Exchange transfusion may have a role in the management of severe haemolysis or in G-6-P-D deficiency associated with life-threatening methaemoglobinaemia where methylene blue is relatively contraindicated.

Thallium toxicity and the role of Prussian blue in therapy.

Abstract: Thallium salts have been used as medicinal agents, as key ingredients in a variety of manufacturing processes, and as a potent rodenticide. Additionally, environmental concerns are growing, as thallium is a waste product of coal combustion and the manufacturing of cement. Thallium salts are rapidly and nearly completely absorbed by virtually all routes, with gastrointestinal exposure being the most common route to produce toxicity. Thallium enters cells by a unique process governed by its similarity in charge and ionic radius to potassium. Although the exact mechanism of toxicity has not been established, thallium interferes with energy production at essential steps in glycolysis, the Krebs cycle, and oxidative phosphorylation. Additional effects include inhibition of sodium-potassium-adenosine triphosphatase and binding to sulfhydryl groups. The major manifestations of toxicity consist of a rapidly progressive, ascending, extremely painful sensory neuropathy and alopecia. Unlike exposure to most metal salts, gastrointestinal symptoms of thallium toxicity are relatively minor, and constipation is more characteristic than diarrhoea. Many other findings such as an autonomic neuropathy, cranial nerve abnormalities, altered mental status, motor weakness, cardiac, hepatic, and renal effects are described, but are less specific. Thallium also crosses the placenta freely and produces abnormalities in animals as well as fetal demise, overt toxicity and congenital abnormalities in humans. There are no controlled trials of treatments in thallium-poisoned patients. Thus, the literature is predominated by very small animal studies and case reports with very limited data. Strong evidence speaks against the use of traditional metal chelators such as dimercaprol (British Anti-Lewisite) and penicillamine, and the latter may cause redistribution of thallium into the central nervous system. Likewise, forced potassium diuresis appears harmful. The use of single- or multiple-dose activated charcoal is supported by in vitro binding experiments and some animal data, and charcoal haemoperfusion may be a useful adjunct. Multiple animal studies give evidence for enhanced elimination and improved survival with Prussian blue. Unfortunately, despite the fact that many humans have been treated with Prussian blue, the data presented are insufficient to comment definitively on its efficacy. However, Prussian blue’s safety profile is superior to that of other proposed therapies and it should be considered the drug of choice in acute thallium poisoning. Public health efforts should focus on greater restrictions on access to, and use of, thallium salts.

Human parathion poisoning. A toxicokinetic analysis.

Abstract: The mortality rate of suicidal parathion poisoning is particularly high, the onset of fulminant cholinergic signs, and the patients frequently present to the emergency physician with life-threatening symptoms. Despite this uniformity, subsequent clinical course differs significantly among patients, mostly not as a result of different delays in treatment or insufficiency of primary care. Probably, the differences depend on the amount of poison absorbed and/or the disposition of the active poison, paraoxon. We followed the toxicokinetics of parathion and tried to quantify the actual poison load. To this end, we monitored parathion-intoxicated patients (patients requiring artificial ventilation) for plasma levels of parathion and paraoxon along with the activity of erythrocyte acetylcholinesterase and its reactivatability. Plasma obidoxime concentrations were followed as well as the cumulative urinary para-nitrophenol conjugate excretion as a measure of total poison load. All patients received a standard obidoxime scheme of a 250 mg bolus dose intravenously, followed by continuous infusion with 750 mg per 24 hours as long as reactivation could be expected (usually 1 week). All other treatment was instituted as judged by the physician. It was recommended to use atropine at low doses to achieve dry mucous membranes, no bronchoconstriction and no bradycardia. Usually 1-2 mg/h were sufficient. Seven selected cases are presented exemplifying toxicokinetic peculiarities. All patients were severely intoxicated, while the amount of parathion absorbed varied widely (between 0.12 and 4.4 g; lethal dose 0.02-0.1 g) and was generally much lower than anticipated from the reports of relatives. It remains open whether the discrepancies between reports and findings were due to exaggeration or to effective decontamination (including spontaneous vomiting, gastric lavage and activated charcoal). Absorption of parathion from the gastrointestinal tract was sometimes retarded, up to 5 days, resulting in fluctuating plasma profiles. The volume of distribution at steady-state (Vdss) of parathion was around 20 L/kg. Post-mortem analysis in one patient revealed a 66-fold higher parathion concentration in fat tissue compared with plasma, 16 days after ingestion. Biotransformation of parathion varied widely and was severely retarded in one patient receiving fluconazole during worsening of renal function, while phenobarbital (phenobarbitone) sedation (two cases) had apparently no effect. The proportion of plasma parathion to paraoxon varied from 0.3-30, pointing also to varying paraoxon elimination, as illustrated by one case with particularly low paraoxonase-1 activity. Obidoxime was effective at paraoxon concentrations below 0.5 microM, provided aging was not too advanced. This concentration correlated poorly with the paration concentration or the poison load. The data are discussed in light of the pertinent literature.

Idiopathic environmental intolerance: Part 1: A causation analysis applying Bradford Hill's criteria to the toxicogenic theory.

Abstract: Idiopathic environmental intolerance (IEI) is a descriptor for a phenomenon that has many names including environmental illness, multiple chemical sensitivity and chemical intolerance. Toxicogenic and psychogenic theories have been proposed to explain IEI. This paper presents a causality analysis of the toxicogenic theory using Bradford Hill's nine criteria (strength, consistency, specificity, temporality, biological gradient, biological plausibility, coherence, experimental intervention and analogy) and an additional criteria (reversibility) and reviews critically the scientific literature on the topic. The results of this analysis indicate that the toxicogenic theory fails all of these criteria. There is no convincing evidence to support the fundamental postulate that IEI has a toxic aetiology; the hypothesised biological processes and mechanisms are implausible.

Tear gases and irritant incapacitants. 1-chloroacetophenone, 2-chlorobenzylidene malononitrile and dibenz[b,f]-1,4-oxazepine.

Abstract: Irritant incapacitants, also called riot control agents, lacrimators and tear gases, are aerosol-dispersed chemicals that produce eye, nose, mouth, skin and respiratory tract irritation. Tear gas is the common name for substances that, in low concentrations, cause pain in the eyes, flow of tears and difficulty in keeping the eyes open. Only three agents are likely to be deployed: (i) 1-chloroacetophenone (CN); (ii) 2-chlorobenzylidene malononitrile (CS); or (iii) dibenz[b,f]-1,4-oxazepine (CR). CN is the most toxic lacrimator and at high concentrations has caused corneal epithelial damage and chemosis. It has accounted for at least five deaths, which have resulted from pulmonary injury and/or asphyxia. CS is a 10-times more potent lacrimator than CN but is less systemically toxic. CR is the most potent lacrimator with the least systemic toxicity and is highly stable. CN, CS and CR cause almost instant pain in the eyes, excessive flow of tears and closure of the eyelids, and incapacitation of exposed individuals. Apart from the effects on the eyes, these agents also cause irritation in the nose and mouth, throat and airways and sometimes to the skin, particularly in moist and warm areas. In situations of massive exposure, tear gas, which is swallowed, may cause vomiting. Serious systemic toxicity is rare and occurs most frequently with CN; it is most likely to occur when these agents are used in very high concentrations within confined non-ventilated spaces. Based on the available toxicological and medical evidence, CS and CR have a large safety margin for life-threatening or irreversible toxic effects. There is no evidence that a healthy individual will experience long-term health effects from open-air exposures to CS or CR, although contamination with CR is less easy to remove.

Sulphur mustard injuries of the skin. Pathophysiology and management.

Abstract: Sulphur mustard is a vesicant (blistering agent), which produces chemical burns with widespread blistering. It was used extensively as a chemical warfare agent in the First World War, and has allegedly been employed in a number of conflicts since then, most recently by Iraq against Iran (1984–1987). The potential further use of mustard in military conflicts and by terrorists remains a significant threat that if realised in practice would result in a large number of casualties with severely incapacitating, partial thickness burns. Such injuries clearly present a huge potential wound care problem.

Human exposure to polychlorinated biphenyls and health effects: a critical synopsis.

Abstract: Polychlorinated biphenyls (PCBs) are a mixture of chemicals. Some congeners of the mixture are highly persistent both in the environment and in humans. Although PCBs have not been used commercially since about 1977 in the US, they can still be detected in human blood and tissues in this country. PCB levels are declining and are often no longer detectable in younger people. A cursory review of recent animal studies is provided. Studies to determine whether PCBs cause cancer in humans, neurobehavioural effects, abnormal thyroid and immune function in children and low birth weight are discussed in more detail. These studies are inconclusive and do not provide clinical evidence that PCBs at levels encountered with human exposure produce adverse health effects. The differences in PCB blood or tissue concentrations between controls and cases, or between the upper and lower end of various environmentally exposed groups of children or adults, are small. Although some effects are statistically significantly different, they do not appear to be biologically significant. Many studies on the effects of PCBs are difficult to interpret because the range of normal values for clinical and neurobehavioural tests are not provided or appropriately considered, there was no, or inadequate, control for potential confounders. In occupational mortality studies, exposures were much higher. In some studies, various specific cancers were elevated. However, these appear to be chance observations resulting from multiple comparisons since the increase of specific cancers was not consistent between studies and was no longer present in some cohorts when studies were repeated at a later date with longer follow-up. Overall, the data fail to demonstrate conclusive adverse health effects of PCBs at concentrations encountered with human exposures.

Poisoning with Amitraz

Abstract: Amitraz, an insecticide and veterinary medicine, has been available in many countries since 1974 but reports of poisoning with it have only become prominent in the last 7 years. The vast majority of cases have occurred in Turkey and have involved children. The data available, both human and animal, do not allow clear separation of the features of toxicity of amitraz from those of the hydrocarbon solvents in which it is commonly dissolved. Amitraz stimulates alpha 2-adrenoceptors resulting in impairment of consciousness, respiratory depression, convulsions, bradycardia, hypotension, hypothermia and hypoglycaemia. Even the most severely poisoned patients recover with nothing more than intensive care; only one possible death has been documented. Animal studies indicate that the alpha 2-adrenoceptor antagonists, yohimbine and atipamezole, can reverse amitraz-induced toxicity but they have not been assessed in poisoned humans.

Diazepam in the Treatment of Organophosphorus Ester Pesticide Poisoning

Abstract: Although the main site of action of diazepam, as with other benzodiazepines, is at the gamma-aminobutyric acid A (GABAA) receptor, the degree to which the beneficial actions of diazepam in organophosphorus (OP) ester pesticide poisoning are mediated through the GABAA receptor has been a matter of controversy. Although in most series of OP intoxications, convulsions have been relatively uncommon, it is probable that convulsions produce long-term sequelae in the central nervous system by causing structural damage. Animal studies have demonstrated that diazepam prevents and treats convulsions produced by OPs and may prevent the late effects caused by damage to the central nervous system induced by such convulsions. Consequently, the use of diazepam is an important part of the treatment regimen of severe OP poisoning as it prevents, or at least reduces the duration of, convulsions. In addition, case reports suggest that diazepam will also ameliorate muscle fasciculation, a subjectively unpleasant feature of OP pesticide poisoning. There are no data, either experimental or clinical, demonstrating any clear effect of diazepam alone on lethality in OP poisoning. In fact, in one study of large animals, diazepam, given alone, increased lethality. In animals experimentally poisoned with OPs, combined treatment with atropine and diazepam significantly lowered lethality compared with atropine treatment alone, indicating a clear beneficial effect. There are numerous case reports of the use of diazepam, generally as an adjunct to other more specific OP antidotes such as atropine and/or pyridinium oximes. Based on this evidence and pharmacodynamic studies in experimental animals, diazepam should be given to patients poisoned with OPs whenever convulsions or pronounced muscle fasciculation are present. In severe poisoning, diazepam administration should be considered even before these complications develop. Although diazepam has a large therapeutic index, there appears to be no place for its routine use in OP poisoning. Diazepam should be given intravenously to patients treated in hospital for OP poisoning, although the intramuscular route is used to administer diazepam outside hospital, such as on the battlefield, when an auto-injector is employed. It should be recognised, however, that absorption by the intramuscular route is poor.

Does Urine Alkalinization Increase Salicylate Elimination? If so, Why?

Abstract: Urine alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate to produce urine with a pH ≥7.5. Experimental and clinical studies confirm that urinary alkalinization increases salicylate elimination, although the mechanisms by which this occurs have not been elucidated. The conventional view is that ionisation of a weak acid, such as salicylic acid, is increased in an alkaline environment. Since the ionisation constant (pKa) is a logarithmic function then, theoretically, a small change in urine pH will have a disproportionately larger effect on salicylate clearance. Hence, elimination of salicylic acid by the kidneys is increased substantially in alkaline urine. However, as salicylic acid is almost completely ionised within physiological pH limits, alkalinization of the urine could not, therefore, significantly increase the extent of ionisation further and the conventional view of the mechanism by which alkalinization is effective is patently impossible. Further experimental studies are required to clarify the mechanisms by which urine alkalinization enhances salicylate elimination.

Pharmacokinetics and blood levels of polychlorinated biphenyls.

Abstract: Despite the enormous number of reports on polychlorinated biphenyl (PCB) toxicology, both the causal interpretation of epidemiological studies and the risk assessment of human exposures have been hampered by the lack of information on the pharmacokinetics of various PCB isomers and congeners. Thus, the assessment of exposure by means of measuring either total PCBs or individual congeners in the blood has so far been unsatisfactory. For example, the concentration and the pattern of congeners in the blood did not correlate with that at site(s) of action. In fact, the same levels of blood PCBs correlated with either toxic effects or no effects (both in clinical and epidemiological studies). In addition, when toxicity caused by PCBs was observed, the severity of the signs did not correlate with blood levels. Reasons for such a qualified failure are manifold and include different ways of reporting blood measurements, the different toxicological characteristics of each PCB, and different timing of sampling the blood, etc. Therefore, only limited conclusions can be drawn concerning what blood PCB measurements mean.

Is There a Causal Relationship Between Exposure to Diesel Exhaust and Multiple Myeloma

Abstract: This article presents a comprehensive critical review of the epidemiology of multiple myeloma in relation to occupational diesel exhaust exposure. The review includes cohort and proportional mortality studies of workers exposed to diesel exhaust, and population-based case-control studies of multiple myeloma. None of the cohort or proportional mortality studies reported a significant increase of multiple myeloma in relation to diesel exhaust, with the exception of a study of Danish truck drivers. Several limitations in this Danish study (such as inadequate cohort identification, small number of multiple myeloma deaths and inappropriate analytical method) made the result unreliable. Furthermore, the data in this study of Danish truck drivers were part of and, hence, superseded by a large study in Denmark, which did not find any increased risk of multiple myeloma. Similarly, none of the case-control studies reported a significant increase of multiple myeloma in relation to diesel exhaust, with the exception of the smallest case-control study based on multiple myeloma patients in central and southeast Sweden. The result of this small Swedish study was not reliable because of incomplete case ascertainment, inappropriate controls and confounding. Furthermore, the data in this small Swedish study were part of and, hence, superseded by a large national study of workers exposed to diesel exhaust in Sweden, which did not find any increased risk of multiple myeloma. Other than the study of Danish truck drivers and the small case-control study of multiple myeloma patients in central and southeast Sweden, all other epidemiological investigations consistently reported no increase of multiple myeloma in relation to occupational diesel exhaust exposure. Furthermore, none of the studies reported a positive exposure-response relationship between diesel exhaust and multiple myeloma. Several studies that analysed data by jobs or occupations according to level of exposure and by duration of exposure did not find any upward trend. In addition to the review, a formal causation analysis based on an application of the Hill criteria confirms that there is no causal relationship between diesel exhaust and multiple myeloma.