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By Laureen Marinetti, PhD, F-ABFT

A therapeutic reference range like those listed on the Axis Forensic Toxicology report (Schulz, M., et al.) is provided as a starting point.  These ranges are derived from the clinical literature regarding an effective range of therapy for a drug, a therapeutic range.  Since they are from clinical data they are commonly measured in plasma or serum and collected from healthy subjects in a controlled study.  These subjects are not infants, children, elderly or individuals in poor health or who abuse drugs.  The samples are not whole blood and are not collected from the heart or a central cavity and they are not decomposed or from an embalmed body.  Changes to drug levels after death are inevitable and unavoidable.  Therefore, trying to compare postmortem concentrations to these clinical data is not comparing apples to apples so to speak.  This is why any value given for a therapeutic, toxic, or lethal blood concentration is not considered absolute, but is to be used as a frame of reference or guideline in evaluating a specific case in its context.   

What about postmortem data from case studies that provide toxic and lethal ranges?  While a reference text such as Baselt is useful in a general sense, these data are not controlled for the many variables inherent in postmortem toxicology.  These variables may include; collection site of the blood (concentrations from central sites may be affected by postmortem redistribution or PMR), the presence of other drugs (may add to or subtract from the toxic effects), tolerance state of the decedent, bacterial activity, genetic polymorphisms, resuscitation efforts, condition of the blood (decomposed or embalmed may lead to a lower concentration than at the time of death), manner of death (suicide vs accidental, the former potentially having an “overkill” drug concentration due to the intent of drug use), survival time (allows for drug metabolism thus lowering the postmortem measured concentration), and time of testing in relation to the sample collection (unstable drugs may degrade before they are tested, especially if the sample is not stored properly).  Therefore, to help answer the million-dollar question; is the concentration and/or combination of drug(s) measured or detected significant to the cause of death, or is it an incidental finding.   

The Academy Standards Board (ASB) developed a guideline for Forensic Toxicologists called Guidelines for Opinions and Testimony in Forensic Toxicology, ANSI/ASB 037.  It states in part that opinions be based on the totality of information available, including case history, observations, circumstances, and other relevant information, and not based solely on analytical results (4.3.c).    To follow the guidelines, the Forensic Toxicologist requires more information such as medical history, autopsy results, and death investigation.  Having this information allows the toxicology results to be put in context of the specific case, thus giving the best answer to the question posed.  Blood drug concentration and drug effects can be affected by the dose of the substance used, length of time between the dose and death, drug metabolism, drug absorption differences, route of administration, how long the drug has been used (tolerance), did the subject stop using the drug and then start again (loss of tolerance), age and sex of the individual, underlying pathology or observed disease states, individual drug stability in blood, postmortem redistribution or PMR (collect a peripheral blood to help minimize PMR), protein binding, and the accumulation of active metabolites.  There is also the first Academy Standards Board standard for Medicolegal Death Investigation entitled, Organizational and Foundational Standard for Medicolegal Death Investigation, ANSI/ASB 125 First Edition, 2021.

Let’s look at some specific drugs and case histories to illustrate the difficulty with the interpretation of toxicology findings.  These examples are nowhere near all inclusive.    

Examples of two drugs that need to be interpreted in context are fentanyl and ketamine.  Both of these drugs are commonly used medically therefore if a decedent is in the hospital or had emergency treatment prior to death, it would be important to have medical records, especially if the case is a suspected drug overdose.  Tolerance or lack of tolerance is one, but not the only, important variable to consider.  Two drugs that result in high tolerance are methadone and fentanyl.  During the time of methadone clinics for heroin treatment, methadone concentrations in tolerant subjects were documented up to 3000 ng/mL, range of 30 to 3000, and ranged from 20 to 2000 in impaired drivers.  Blood concentrations found in the postmortem blood of people who died from methadone toxicity ranged from 60 to 3100 ng/mL.  These large, overlapping ranges can possibly be explained by tolerance, but PMR and the presence of other central nervous system (CNS) depressant drugs can also play a role.  Also, underlying disease can result in a subject being more sensitive to a drug’s toxic effects. Methadone is cardio-toxic therefore those with cardiac disease may be more sensitive to methadone toxicity than those that do not have cardiac disease. 

Fentanyl was predominately used in a medical setting; the first abuse of fentanyl was diversion of the medical product.  In that time a fentanyl therapeutic range from clinical data was 0.3 to 3.8 ng/mL, therefore a value of 8 ng/mL or more was thought to be a possible cause or at least contributory to death.  However since the mass abuse of the illicitly manufactured fentanyl, the concentration of fentanyl in ante-mortem toxicology case work has been increasing.  Driving under the influence of drugs data is a great way to gain an appreciation of tolerance in the user population.  In a study of 186 living subjects from driving under the influence of drugs case work, showed fentanyl concentrations ranging from 0.5 to 303 ng/mL, with a mean of 11.8 and median of 5.5 ng/mL (hospital records were reviewed to exclude those cases in which fentanyl was administered).  In this same study there were 238 central blood samples from postmortem cases where fentanyl was listed in the COD which showed a range of 0.7 to 636 ng/mL with a mean of 32.5 and a median of 19.3, and 58 peripheral blood samples from postmortem cases which showed a range of 0.9 to 78 ng/mL with a mean of 14 and a median of 10.  As shown by this data, fatal and impairing concentrations of fentanyl overlap and the clinical therapeutic range determined years ago no longer applies to most fentanyl cases today.  A review of the autopsy and investigation findings is important for fentanyl positive cases.   

For those decedents with a history of respiratory conditions, opioids like fentanyl and other drugs that cause central nervous system depression can be fatal at lower concentrations.  Decedents with cardiovascular or hypertensive disease are more sensitive to the toxic effects of stimulant drugs like cocaine, methamphetamine, MDMA, pseudoephedrine, caffeine, etc.  Drugs whose toxic effects include seizures can lower the threshold of toxicity if the decedent already has a seizure disorder. While the drug may not be the direct cause of death, it may be contributory to the death in combination with the underlying disease state.  There are many variables to consider in each case and there is no one size fits all type of reference range for forensic toxicology testing nor should there be.  The interpretation hinges on the context and circumstances of the specific case. Axis Forensic Toxicology understands that one should never practice toxicology strictly by the numbers and we are able to help with interpretation of the toxicology results in your case work.  If you have any questions or concerns regarding a substance’s role in your medicolegal death investigation, please reach out to our subject matter experts at [email protected]. 

“All things are poisons, for there is nothing without poisonous qualities.  It is only the dose which makes a thing poison.” (Paracelsus).   

References 

• ANSI/ASB 037, Guidelines for Opinions and Testimony in Forensic Toxicology, 2019. https://www.aafs.org/asb-standard/guidelines-opinions-and-testimony-forensic-toxicology 
• ANSI/ASB 125, Organizational and Foundational Standard for Medicolegal Death Investigation, 2021.  https://www.aafs.org/asb-standard/organizational-and-foundational-standard-medicolegal-death-investigation
• Baselt, Randall C., Disposition of Toxic Drugs and Chemicals in Man, 12th Edition, Biomedical Publications, 2020.  
• Havro, V., Casassa, N., Andera, K., and Mata, D., A Two-Year Review of Fentanyl in Driving under the Influence and Postmortem Cases in Orange County, CA, USA., Journal of Analytical Toxicology, Vol. 46, Issue 8, October 2022, pp. 875-881. 
• Rohrig, Timothy P., Postmortem Toxicology Challenges and Interpretive Considerations, Elsevier Academic Press, 2019. 
• Schulz, M., Iwersen-Bergmann, S.,Andresen, H.,and Schmoldt, A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics, Critical Care, 2012, 16:R136. 
• Stephenson, L., Van Den Heuvel, C., Scott, T., and Byard, R.W., Difficulties Associated with the Interpretation of Postmortem Toxicology, Journal of Analytical Toxicology, Vol. 48, Issue 6, July 2024, pp. 405-412. 

By Kevin G. Shanks, M.S., D-ABFT-FT  

Axis Forensic Toxicology prides itself in its ability and willingness to provide continuing education and training for our forensic toxicology clients. One of these educational avenues is the Axis forensic medicine fellow training rotation program. We are planning now for our Spring 2025 program.

In this weeklong virtual training program, a Forensic Medicine Fellow will be introduced to the set-up and operation of the modern postmortem forensic toxicology laboratory, alongside descriptions of the analytical instrumentation and analytical methods employed by the laboratory. Board certified forensic toxicologists will discuss the importance of toxicology specimen collection and present a survey of the major illicit and pharmaceutical drugs (e.g. ethanol, cocaine, methamphetamine, MDMA, heroin, fentanyl, and prescription opioids) with respect to mechanisms of actions, their detection, and their relevance to cause of death determination. Novel psychoactive substances (NPS), to include designer benzodiazepines, synthetic cannabinoids, substituted cathinones, fentanyl analogs, nitazene derivatives, xylazine, and mitragynine (kratom) are also discussed in depth. 

The forensic toxicology forensic medicine fellow training rotation instills the Fellow with confidence in interpreting the significance of toxicological findings with respect to cause and manner of death classification. Peer reviewed scientific references provided to the Fellow lay a foundation for a body of knowledge that may aid in the resolution of drug-related deaths by the forensic pathologist. One-on-one toxicology case review with a forensic toxicologist surveying completed cases by the laboratory will be undertaken and is intended to give the Fellow an overview of how a “toxicology pending conference” is conducted between forensic pathologists and forensic toxicologists. 

If you are a forensic pathology fellow or a pathologist who directs forensic pathology fellows and are interested in learning more about this training opportunity, please reach out to Axis Forensic Toxicology’s toxicologists at [email protected] or call us on the phone at (317) 759 – 4869.