By Kevin Shanks, D-ABFT-FT
Many forensic toxicology tests are qualitative and provide a positive-negative or present-not detected result. The interpretation of those results is relatively simple. A substance is there or it is not. But, a quantitative test with a numerical result must be put into context of the case to aid in determining its overall meaning. Is the concentration of drug measured significant to the investigation or is it an incidental finding? Forensic toxicologists do this by compiling reference ranges, or sets of blood, serum, or plasma drug or metabolite concentrations which are used as a baseline for interpretation of results.
A therapeutic blood concentration is a concentration or level of drug or its active metabolite which is present in the blood, serum, or plasma following a therapeutically effective dosage. Most therapeutic ranges originate from data amassed during pharmaceutical medication clinical trials or controlled dosing studies. More often than not, the individuals tested to determine a therapeutic blood range consist of a healthy, non-disease stricken population. A toxic blood concentration is a concentration or level of drug or its active metabolite present in the blood, serum, or plasma that is associated with serious adverse or toxic symptoms. A lethal blood concentration is an amount of drug or its active metabolite present in the blood, serum, or plasma that has been reported to cause fatality, or is so far above reported therapeutic or toxic concentrations, that one may judge it might cause fatality.
Test tubes and other recipients in chemistry lab by Horia Varlan (CC BY 2.0)
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. Blood concentrations can be affected by dose of the substance used, route of administration, drug absorption differences, age and sex of the individual, potential tolerance to the substance, underlying pathology or observed disease states, postmortem redistribution (PMR), substance protein binding, and the accumulation of active metabolites.
Some substances have distinct therapeutic, toxic, and lethal blood reference ranges. This can be shown by looking at acetaminophen (Tylenol). Acetaminophen’s therapeutic reference range is 10-30 mcg/mL while it’s toxic and lethal reference ranges are greater than 150 mcg/mL. As you can see, there is a definite difference observed in the reference ranges.
On the other hand, some substances have overlapping therapeutic, toxic, and lethal blood reference ranges. The reported therapeutic reference range for fentanyl in blood is 1-3 ng/mL. But toxicity may occur at blood concentrations lower than 3 ng/mL. People using fentanyl as a therapeutic medication under the supervision of a physician may also regularly have blood concentration exceeding 3 ng/mL. Another example of this overlap in therapeutic and toxic/lethal ranges is methadone. Acute oral therapeutic dosing of methadone in treatment settings has resulted in blood concentrations 75-860 ng/mL and chronic oral dosing of methadone in medical treatment settings has led to blood concentrations 570-1,006 ng/mL. But, blood concentrations found in the postmortem blood of people who have died from methadone toxicity were 20-5,300 ng/mL.
There is no one size fits all type of reference range for forensic toxicology testing – the interpretation hinges on the context and circumstances of the 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 relevant toxicology in your casework.
Axis is making changes to its final toxicology reports to align with and provide a single source of values for the reported reference ranges. If you have any questions or concerns regarding a substance’s reference range or its role in your medical-legal death investigation, please reach out to our subject matter experts at [email protected].
References
Disposition of Toxic Drugs and Chemicals in Man. Twelfth Edition. Randall C. Baselt. Biomedical Publications. (2020).
Pharmacokinetics and Pharmacodynamics. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. American Association for Clinical Chemistry (AACC). 2017. 77-93.
Introduction to Forensic Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 1-12. (2008).
Postmortem Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 191-218. (2008).
Postmortem Forensic Toxicology. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. AACC, Inc. Pages 3-14. (2017).