Merete Vevelstad

Lethal methemoglobinemia and automobile exhaust inhalation

Inhalation of automobile exhaust gas often leads to death by CO intoxication. In some cases the measured carbon monoxide hemoglobin saturation level (COHb) is considerably below what is considered to be lethal. The death in such cases has been attributed to a combination of a high CO2 and a low O2 tension. In a recent case the deceased was found dead in a car equipped with a catalytic converter, with a hose leading exhaust from the engine to the interior of the car. Analysis revealed a moderately elevated COHb and a high methemoglobin saturation level (MetHb) in peripheral blood. No ethanol, narcotics or drugs were detected. Reports mentioning MetHb or methemoglobinemia in post-mortem cases are surprisingly scarce, and very few have related exhaust gas deaths to methemoglobinemia. High-degree methemoglobinemia causes serious tissue hypoxia leading to unconsciousness, arrhythmia and death. The existing literature in this field and the knowledge that exhaust fumes contain nitrogen oxide gases (NOx) that by inhalation and absorption can result in severe methemoglobinemia, led us to postulate that this death could possibly be attributed to a combination of methemoglobinemia and a moderately high COHb concentration.

Codeine to Morphine Concentration Ratios in Samples from Living Subjects and Autopsy Cases after Incubation

The codeine to morphine concentration ratio is used in forensic toxicology to assess if codeine has been ingested alone or if morphine and/or heroin have been ingested in addition. In our experience, this interpretation is more difficult in autopsy cases compared with samples from living persons, since high morphine concentrations are observed in cases where only codeine is assumed to have been ingested. We have investigated if codeine and morphine glucuronides are subject to cleavage to the same extent in living and autopsy cases in vitro. We included whole blood samples from eight living subjects and nine forensic autopsy cases, where only codeine ingestion was suspected. All samples were incubated for 2 weeks at 37°C and analyzed for codeine and six codeine metabolites using liquid chromatography tandem mass spectrometry. A reduction in the codeine to morphine concentration ratio was found, both in samples from living subjects (mean 33%, range 22-50%) and autopsy cases (mean 37%, range 13-54%). The increase in the morphine concentrations was greater in the autopsy cases (mean 85%, max 200%) compared with that of the living cases (mean 51%, max 87%). No changes were seen for codeine or codeine-6-glucuronide concentrations. The altered ratios might mislead the forensic toxicologist to suspect morphine or heroin consumption in cases where only codeine has been ingested.

Novel psychoactive substances.

There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel Psychoactive Substances, and are mainly sold over the Internet. Uncertain dosage of potent substances entails a risk of accidental overdose, and therefore serious intoxication and death. In this article we provide an overview of current knowledge with regard to these substances.

Is toxicity of PMMA (paramethoxymethamphetamine) associated with cytochrome P450 pharmacogenetics

In 2010-2013, 29 fatal intoxications related to the designer drug paramethoxymethamphetamine (PMMA, 4-methoxymethamphetamine) occurred in Norway. The current knowledge about metabolism and toxicity of PMMA in humans is limited. Metabolism by the polymorphic cytochrome P450 (CYP) 2D6 enzyme to the psychoactive metabolite 4-hydroxymethamphetamine (OH-MA), and possibly by additional enzymes, is suggested to be involved in its toxicity. The aim of this work was to study the association between CYP genetics, PMMA metabolism and risk of fatal PMMA toxicity in humans. The frequency distribution of clinically relevant gene variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A5, and the phenotypic blood CYP2D6 metabolic ratio (OH-MA/PMMA) in particular, were compared in fatal PMMA intoxications (n=17) and nonfatal PMMA abuse controls (n=30), using non-abusers (n=305) as references for the expected genotype frequencies in the Norwegian population. Our study demonstrated that the CYP2D6 enzyme and genotype are important in the metabolism of PMMA to OH-MA in humans, but that other enzymes are also involved in this biotransformation. In the fatal PMMA intoxications, the blood concentrations of PMMA were higher and the CYP2D6 metabolic ratios were lower, than in the nonfatal PMMA abuse controls (median (range) 2.1 (0.03-5.0) vs 0.3 (0.1-0.9) mg/L, and ratio 0.6 (0.0-4.6) vs 2.1 (0.2-7.4) p=0.021, respectively). Overall, our findings indicated that, in most cases, PMMA death occurred rapidly and at an early stage of PMMA metabolism, following the ingestion of large and toxic PMMA doses. We could not identify any genetic CYP2D6, CYP2C9, CYP2C19 or CYP3A5 predictive marker on fatal toxicity of PMMA in humans. The overrepresentation of the CYP2D6 poor metabolizer (PM) genotype found in the nonfatal PMMA abuse controls warrants further investigations.

Asphyxiation death caused by oxygen-depleting cargo on a ship

The extreme danger associated with entering enclosed spaces loaded with oxygen-depleting organic cargo in ships and tanks is obviously underestimated, both among crew and management. We present a case report to highlight this occupational hazard and to increase the knowledge about the imperative precautions, in order to prevent future accidents. An experienced customs officer was found lifeless at the bottom of the unattended cargo hold on a ship loaded with woodchips. The oxygen content in the cargo atmosphere was below 2%, which is incompatible with life. Forensic autopsy revealed injuries related to the fall, and there were no positive toxicological findings in blood, lung or urine. Management and workers must be taught about the extreme rapidity of developing unconsciousness and asphyxiant death when entering enclosed spaces loaded with oxygen-depleting cargo. Even a single inhalation can result in unconsciousness and death. Dozens of annual deaths and severe injuries can easily be prevented if simple precautions are followed.

Studies on Para-Methoxymethamphetamine (PMMA) Metabolite Pattern and Influence of CYP2D6 Genetics in Human Liver Microsomes and Authentic Samples from Fatal PMMA Intoxications

Para-methoxymethamphetamine (PMMA) has caused numerous fatal poisonings worldwide and appears to be more toxic than other ring-substituted amphetamines. Systemic metabolism is suggested to be important for PMMA neurotoxicity, possibly through activation of minor catechol metabolites to neurotoxic conjugates. The aim of this study was to examine the metabolism of PMMA in humans; for this purpose, we used human liver microsomes (HLMs) and blood samples from three cases of fatal PMMA intoxication. We also examined the impact of CYP2D6 genetics on PMMA metabolism by using genotyped HLMs isolated from CYP2D6 poor, population-average, and ultrarapid metabolizers. In HLMs, PMMA was metabolized mainly to 4-hydroxymethamphetamine (OH-MA), whereas low concentrations of para-methoxyamphetamine (PMA), 4-hydroxyamphetamine (OH-A), dihydroxymethamphetamine (di-OH-MA), and oxilofrine were formed. The metabolite profile in the fatal PMMA intoxications were in accordance with the HLM study, with OH-MA and PMA being the major metabolites, whereas OH-A, oxilofrine, HM-MA and HM-A were detected in low concentrations. A significant influence of CYP2D6 genetics on PMMA metabolism in HLMs was found. The catechol metabolite di-OH-MA has previously been suggested to be involved in PMMA toxicity. Our studies show that the formation of di-OH-MA from PMMA was two to seven times lower than from an equimolar dose of the less toxic drug MDMA, and do not support the hypothesis of catechol metabolites as major determinants of fatal PMMA toxicity. The present study revealed the metabolite pattern of PMMA in humans and demonstrated a great impact of CYP2D6 genetics on human PMMA metabolism.