Analysis of fatal poisonings due to toxic alcohols and drugs : focus on metabolites

Jenni Viinamäki

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

In Finland, 800-900 deaths are caused by fatal poisonings due to drugs or alcohols annually. Of these, around ten are caused by toxic alcohols, mainly methanol and ethylene glycol, and 400-500 are caused by drugs, both medicinal and illicit. Despite the fact that the majority of fatal poisonings are caused by relatively few individual compounds, toxicological laboratories must be capable of identifying and quantifying a wide range of possible toxicants. Small sample volumes and post-mortem changes impose special demands on both the laboratory investigation and the interpretation of results. The two main objectives of the present thesis are, first, to develop new analytical laboratory methods for toxic alcohols and drugs and, second, to apply these methods to post-mortem toxicology cases in order to generate reference data on lethal concentrations of especially metabolites for interpretation purposes. Metabolites of toxic substances constitute an interpretive resource that is far from fully exploited in post-mortem toxicology. The therapeutic, toxic, and lethal concentrations of alcohols and drugs are usually expressed as the concentration of the parent compound in blood. Yet the toxicity of methanol and ethylene glycol, for example, is mainly caused by their toxic metabolites and many therapeutic drugs are transformed to metabolites that possess pharmacological activity similar to or greater than that of the parent drug. A method for the quantitative analysis of ethylene glycol, glycolic acid, and formic acid and for the screening of volatile and hydroxylic organic compounds was developed, using headspace in-tube extraction gas chromatography-mass spectrometry. In fatal poisonings by methanol or ethylene glycol, the concentration of the parent alcohol varied significantly, whereas the concentrations of formic acid and glycolic acid in blood were found to be more uniform. Fatal metabolite threshold concentrations were established for those poisoning cases that had not received hospital treatment. In cases involving putrefaction, significant post-mortem production of formic acid was detected, and consequently the concentrations of metabolites should always be interpreted together with those of the parent alcohols. A comprehensive method for the quantitative monitoring of over 150 basic drugs and metabolites in blood samples was developed utilizing ultra-high performance liquid chromatography coupled with two consecutive detectors: diode array detector and corona charged aerosol detector (UHPLC-DAD-CAD). Based on the universal response of CAD, the method was evaluated for the quantification of drug metabolites using a secondary calibration method with the corresponding parent drug as a calibration standard. This approach offers a straightforward way of quantifying especially N-demethylated metabolites. It was found that the metabolite to parent ratios of certain toxicologically relevant drugs in post-mortem blood samples were generally comparable to the standard ratios defined in clinical therapeutic drug monitoring. With the highest post-mortem parent drug concentrations, the ratios were below the clinical normal ranges, suggesting acute ingestion or poisoning. These findings encourage forensic toxicologists to actively use the metabolite to parent ratio in the interpretation of post-mortem toxicology results.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-2471-5
Electronic ISBNs978-951-51-2472-2
Publication statusPublished - 2016
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 319 Forensic science and other medical sciences

Cite this

Viinamäki, J. (2016). Analysis of fatal poisonings due to toxic alcohols and drugs : focus on metabolites. Helsinki : University of Helsinki.
Viinamäki, Jenni. / Analysis of fatal poisonings due to toxic alcohols and drugs : focus on metabolites. Helsinki : University of Helsinki, 2016. 70 p.
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title = "Analysis of fatal poisonings due to toxic alcohols and drugs : focus on metabolites",
abstract = "In Finland, 800-900 deaths are caused by fatal poisonings due to drugs or alcohols annually. Of these, around ten are caused by toxic alcohols, mainly methanol and ethylene glycol, and 400-500 are caused by drugs, both medicinal and illicit. Despite the fact that the majority of fatal poisonings are caused by relatively few individual compounds, toxicological laboratories must be capable of identifying and quantifying a wide range of possible toxicants. Small sample volumes and post-mortem changes impose special demands on both the laboratory investigation and the interpretation of results. The two main objectives of the present thesis are, first, to develop new analytical laboratory methods for toxic alcohols and drugs and, second, to apply these methods to post-mortem toxicology cases in order to generate reference data on lethal concentrations of especially metabolites for interpretation purposes. Metabolites of toxic substances constitute an interpretive resource that is far from fully exploited in post-mortem toxicology. The therapeutic, toxic, and lethal concentrations of alcohols and drugs are usually expressed as the concentration of the parent compound in blood. Yet the toxicity of methanol and ethylene glycol, for example, is mainly caused by their toxic metabolites and many therapeutic drugs are transformed to metabolites that possess pharmacological activity similar to or greater than that of the parent drug. A method for the quantitative analysis of ethylene glycol, glycolic acid, and formic acid and for the screening of volatile and hydroxylic organic compounds was developed, using headspace in-tube extraction gas chromatography-mass spectrometry. In fatal poisonings by methanol or ethylene glycol, the concentration of the parent alcohol varied significantly, whereas the concentrations of formic acid and glycolic acid in blood were found to be more uniform. Fatal metabolite threshold concentrations were established for those poisoning cases that had not received hospital treatment. In cases involving putrefaction, significant post-mortem production of formic acid was detected, and consequently the concentrations of metabolites should always be interpreted together with those of the parent alcohols. A comprehensive method for the quantitative monitoring of over 150 basic drugs and metabolites in blood samples was developed utilizing ultra-high performance liquid chromatography coupled with two consecutive detectors: diode array detector and corona charged aerosol detector (UHPLC-DAD-CAD). Based on the universal response of CAD, the method was evaluated for the quantification of drug metabolites using a secondary calibration method with the corresponding parent drug as a calibration standard. This approach offers a straightforward way of quantifying especially N-demethylated metabolites. It was found that the metabolite to parent ratios of certain toxicologically relevant drugs in post-mortem blood samples were generally comparable to the standard ratios defined in clinical therapeutic drug monitoring. With the highest post-mortem parent drug concentrations, the ratios were below the clinical normal ranges, suggesting acute ingestion or poisoning. These findings encourage forensic toxicologists to actively use the metabolite to parent ratio in the interpretation of post-mortem toxicology results.",
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author = "Jenni Viinam{\"a}ki",
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year = "2016",
language = "English",
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Analysis of fatal poisonings due to toxic alcohols and drugs : focus on metabolites. / Viinamäki, Jenni.

Helsinki : University of Helsinki, 2016. 70 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Analysis of fatal poisonings due to toxic alcohols and drugs : focus on metabolites

AU - Viinamäki, Jenni

N1 - M1 - 70 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2016

Y1 - 2016

N2 - In Finland, 800-900 deaths are caused by fatal poisonings due to drugs or alcohols annually. Of these, around ten are caused by toxic alcohols, mainly methanol and ethylene glycol, and 400-500 are caused by drugs, both medicinal and illicit. Despite the fact that the majority of fatal poisonings are caused by relatively few individual compounds, toxicological laboratories must be capable of identifying and quantifying a wide range of possible toxicants. Small sample volumes and post-mortem changes impose special demands on both the laboratory investigation and the interpretation of results. The two main objectives of the present thesis are, first, to develop new analytical laboratory methods for toxic alcohols and drugs and, second, to apply these methods to post-mortem toxicology cases in order to generate reference data on lethal concentrations of especially metabolites for interpretation purposes. Metabolites of toxic substances constitute an interpretive resource that is far from fully exploited in post-mortem toxicology. The therapeutic, toxic, and lethal concentrations of alcohols and drugs are usually expressed as the concentration of the parent compound in blood. Yet the toxicity of methanol and ethylene glycol, for example, is mainly caused by their toxic metabolites and many therapeutic drugs are transformed to metabolites that possess pharmacological activity similar to or greater than that of the parent drug. A method for the quantitative analysis of ethylene glycol, glycolic acid, and formic acid and for the screening of volatile and hydroxylic organic compounds was developed, using headspace in-tube extraction gas chromatography-mass spectrometry. In fatal poisonings by methanol or ethylene glycol, the concentration of the parent alcohol varied significantly, whereas the concentrations of formic acid and glycolic acid in blood were found to be more uniform. Fatal metabolite threshold concentrations were established for those poisoning cases that had not received hospital treatment. In cases involving putrefaction, significant post-mortem production of formic acid was detected, and consequently the concentrations of metabolites should always be interpreted together with those of the parent alcohols. A comprehensive method for the quantitative monitoring of over 150 basic drugs and metabolites in blood samples was developed utilizing ultra-high performance liquid chromatography coupled with two consecutive detectors: diode array detector and corona charged aerosol detector (UHPLC-DAD-CAD). Based on the universal response of CAD, the method was evaluated for the quantification of drug metabolites using a secondary calibration method with the corresponding parent drug as a calibration standard. This approach offers a straightforward way of quantifying especially N-demethylated metabolites. It was found that the metabolite to parent ratios of certain toxicologically relevant drugs in post-mortem blood samples were generally comparable to the standard ratios defined in clinical therapeutic drug monitoring. With the highest post-mortem parent drug concentrations, the ratios were below the clinical normal ranges, suggesting acute ingestion or poisoning. These findings encourage forensic toxicologists to actively use the metabolite to parent ratio in the interpretation of post-mortem toxicology results.

AB - In Finland, 800-900 deaths are caused by fatal poisonings due to drugs or alcohols annually. Of these, around ten are caused by toxic alcohols, mainly methanol and ethylene glycol, and 400-500 are caused by drugs, both medicinal and illicit. Despite the fact that the majority of fatal poisonings are caused by relatively few individual compounds, toxicological laboratories must be capable of identifying and quantifying a wide range of possible toxicants. Small sample volumes and post-mortem changes impose special demands on both the laboratory investigation and the interpretation of results. The two main objectives of the present thesis are, first, to develop new analytical laboratory methods for toxic alcohols and drugs and, second, to apply these methods to post-mortem toxicology cases in order to generate reference data on lethal concentrations of especially metabolites for interpretation purposes. Metabolites of toxic substances constitute an interpretive resource that is far from fully exploited in post-mortem toxicology. The therapeutic, toxic, and lethal concentrations of alcohols and drugs are usually expressed as the concentration of the parent compound in blood. Yet the toxicity of methanol and ethylene glycol, for example, is mainly caused by their toxic metabolites and many therapeutic drugs are transformed to metabolites that possess pharmacological activity similar to or greater than that of the parent drug. A method for the quantitative analysis of ethylene glycol, glycolic acid, and formic acid and for the screening of volatile and hydroxylic organic compounds was developed, using headspace in-tube extraction gas chromatography-mass spectrometry. In fatal poisonings by methanol or ethylene glycol, the concentration of the parent alcohol varied significantly, whereas the concentrations of formic acid and glycolic acid in blood were found to be more uniform. Fatal metabolite threshold concentrations were established for those poisoning cases that had not received hospital treatment. In cases involving putrefaction, significant post-mortem production of formic acid was detected, and consequently the concentrations of metabolites should always be interpreted together with those of the parent alcohols. A comprehensive method for the quantitative monitoring of over 150 basic drugs and metabolites in blood samples was developed utilizing ultra-high performance liquid chromatography coupled with two consecutive detectors: diode array detector and corona charged aerosol detector (UHPLC-DAD-CAD). Based on the universal response of CAD, the method was evaluated for the quantification of drug metabolites using a secondary calibration method with the corresponding parent drug as a calibration standard. This approach offers a straightforward way of quantifying especially N-demethylated metabolites. It was found that the metabolite to parent ratios of certain toxicologically relevant drugs in post-mortem blood samples were generally comparable to the standard ratios defined in clinical therapeutic drug monitoring. With the highest post-mortem parent drug concentrations, the ratios were below the clinical normal ranges, suggesting acute ingestion or poisoning. These findings encourage forensic toxicologists to actively use the metabolite to parent ratio in the interpretation of post-mortem toxicology results.

KW - Alcohols

KW - +analysis

KW - Autopsy

KW - +methods

KW - Carboxylic Acids

KW - Cause of Death

KW - Chemical Fractionation

KW - Chromatography, High Pressure Liquid

KW - Ethylene Glycol

KW - Forensic Toxicology

KW - Formates

KW - Gas Chromatography-Mass Spectrometry

KW - Glycolates

KW - Methanol

KW - +poisoning

KW - MPTP Poisoning

KW - Pharmaceutical Preparations

KW - +blood

KW - Poisoning

KW - +diagnosis

KW - Postmortem Changes

KW - Solvents

KW - Spectrometry, Mass, Electrospray Ionization

KW - Volatile Organic Compounds

KW - +urine

KW - 319 Forensic science and other medical sciences

M3 - Doctoral Thesis

SN - 978-951-51-2471-5

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

CY - Helsinki

ER -

Viinamäki J. Analysis of fatal poisonings due to toxic alcohols and drugs : focus on metabolites. Helsinki : University of Helsinki, 2016. 70 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 65/2016).