GENERATION AND USE OF POST-MORTEM TOXICOLOGY DATA

1. GENERATION AND USE OF POST-MORTEM TOXICOLOGY DATA EAPCCT International Congress Athens, 2 May 2007 Erkki Vuori, professor Department of Forensic Medicine University of Helsinki

2. FORENSIC TOXICOLOGY • ”The study and practice of the application of toxicology to the purposes of law” • The task is to produce valid toxicological information for the administration of justice and to improve the legal protection of individuals and society. • As to the analysis of human samples, there are two key questions: • Has the person under investigation been exposed foreign substances • Has s/he been under the influence of alcohol, drugs or other xenobiotics.

3. FORENSIC TOXICOLOGY 2 • Investigation of living persons • Driving under the influence of alcohol or drugs • Clinical forensic toxicology • Victims and offenders of assault • Drug-facilitated crime • Drug-running • Child welfare • Drunkenness in the workplace • Drug testing programs • Workplace • Schools • Armed forces • Correctional facilities • Treatment of drug-dependent persons • Post-mortem toxicology

4. POST-MORTEM TOXICOLOGY • Analytical results of a post-mortem investigation are utilized to determine the cause and manner of death. • Poisoning can be the: • Underlying cause of death (WHO Ic ”initiated the train of morbid events leading directly to death”) • Immediate cause of death (WHO Ia ”condition with the symptoms of which the deceased died”) • Contributing cause of death (WHO II) • Traditionally, the results of a single forensic case are used for the sake of the deceased in question only. • Over time, cases accumulate to form a greater whole, which can provide information that goes far beyond the original purpose of the routine casework.

5. EPIDEMIOLOGICAL STUDIES, REQUIREMENTS • The results should be derived annually from a known population or area. • The analytical practices of the laboratory should be known and should remain stable over years. • Scope and sensitivity of drug screening (“cut offs”) • Interpretation of the analytical results • If several laboratories are involved in an area the detection limits and analytical principles should be compatible and known • The laboratory should have an information management system • In prospective studies, the questions to be studied can be set out beforehand, while in retrospective studies they must fit with the existing data.

6. FINLAND YEAR 2004, STATISTICS • Inhabitants 5.23 millions • Number of deaths 47,757 • Number of forensic autopsies 11,371 (23.8%) • Number of clinical autopsies 3,952 (8.3%) • Number of toxicogical analyses 6,109 (12.8%)

7. FINLAND IS AN IDEAL COUNTRY FOR POST-MORTEM TOXICOLOGICAL INVESTIGATIONS • High autopsy rate • Extensive use of post-mortem toxicological services • All post-mortem toxicology is centralized to one laboratory by law • The screening methods are comprehensive and have been accredited since 1997 • The laboratory gets as feedback a copy of the death certificate from all cases investigated • The laboratory has an information management system with demographic data • The National Agency for Medicines publishes statistics annually on the consumption of medicines

8. TYPICAL FEATURES OF FATAL DRUG POISONINGS • Frequently several drugs are present • Frequently alcohol has been taken simultaneously • Frequently the victim has committed suicide • Drugs of abuse are common • Victims include young people also

9. THE MOST IMPORTANT FINDING • A combination of several drugs is typically found in the same subject. • If all findings are included in the classification, the number of possible fatal combinations is too high. • The forensic pathologist always has a possibility to choose the most important finding. • If not stated, the drug which has the greatest ratio of found concentration in relation to its therapeutic concentration is taken as the basis of the classification • The method used is a crude mathematical procedure • However, this yields reasonable results from year to year and a similar ranking of the most dangerous drugs

10. THE ATC CLASSIFICATION SYSTEM • Classifies drugs according to anatomical, therapeutic and chemical properties • Gives every drug an individual code comprised of letters and numbers • The first letter indicates the therapeutic system C = cardiovascular system, N = nervous system • The next numbers and letters specify the group and finally the specific drug N05A = antipsychotics, N05AA = phenothiazine with aliphatic side chain, N05AA01= chlorpromazine • Gives also defined daily doses (DDD) • Gives also the consumption of drugs as the DDD per 1000 inhabitants per day, calculated from the number of wholesale sales to pharmacies

11. FATAL POISONINGS ACCORDING TO THE MOST IMPORTANT FINDING IN 2003-2005

12. THE MOST COMMON DRUGS IN FATAL POISONINGS IN FINLAND 2003-2005

13. ESTIMATION OF FATAL TOXICITY • Different methods have been used to relate the deaths by poisoning to the consumption of drugs since 1974 • The ”fatal toxicity index”by Cassidy and Henry (1987) is defined as the ratio of the number of deaths divided by the number of prescriptions (in millions) or by the number of standard quantity units prescribed or by the weight of drug prescribed. • The ”fatality rate”by Farmer and Pinder (1989) is the number of deaths divided by the estimated number of prescriptions (in millions) • The ”fatality ratio”by Vuori et al. (1989) is defined as fatalities divided by DDD per 1000 inhabitants per day

14. ESTIMATION OF FATAL TOXICITY, CONT. • Fatal poisonings depend on the intrinsic toxicity and availability of drugs. • By controlling drug availability, it is possible to compare intrinsic toxicity. • In general, different estimations give a similar ranking of drugs in fatal poisonings, whether calculated against the number of prescriptions or the sales of drugs. • Limitations • If the number of prescriptions is used, over-the-counter drugs cannot be included. • Indices cannot be calculated for drugs of abuse that are also available on the streets

15. THE MOST DANGEROUS CATEGORY OF DRUGS IN FINLAND IN 2004

16. THE MOST DANGEROUS DRUG IN FINLAND IN 2004

17. THE FATALITY INDEX OF SOME HYPNOTICS AND SEDATIVES IN 2002-2005

18. CASE: PROMAZINE

19. CASE: ANTIDEPRESSANTS IN 2003-2005

20. CASE: ANTIDEPRESSANTS IN 2003-2005

21. ANTIDEPRESSANTS: WHY DO THEY BEHAVE DIFFERENTLY? • Not because of poor analytics • The unit DDD per 1000 inhabitants per day is calculated based on the sales from pharmacies • Some antidepressants are prescribed for other indications than depression • Prescription habits: Are the drugs selected according to severity of depression or to different types of patients? • The intrinsic toxicity of the drugs varies.

22. ALCOHOL – DRUG INTERACTIONS, STATISTICAL EVALUATION • Alcohol is a frequent finding in post-mortem toxicology. In Finland, about 50% of forensic cases have a BAC >0.5 o/oo • Alcohol has a non-specific membrane effect and shares a specific effect with many drugs via the GABA receptor • Propoxyphene, amitriptyline and barbiturates are known to be more toxic when used together with alcohol • We conducted a study of behavior of ten common drugs together with alcohol and compared the BAC in these cases against pure fatal alcohol poisonings (Koski et al. 2003)

23. ALCOHOL – DRUG INTERACTIONS

24. FTIs vs. deviations of median BAC in drug-alcohol poisonings from that found in pure alcohol poisonings the bars represent the 95% CIs for the difference in BAC

25. SUMMARY • Today, forensic toxicology is not restricted only to revealing homicides by poisoning, but provides to the society information that is otherwise difficult or impossible to obtain. • Exploits the results of ”natural experiments” for the benefit of living human beings. • The results can be used to • evaluate drug safety • reveal differences in the intrinsic toxicity of drugs and thereby to rank the drugs • reveal the abuse potential of therapeutic drugs • follow prescription practices • study drug/alcohol or drug/drug interactions on a statistical basis