Forensic Medicine & Applied Toxicology-7

Category: Education

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Presentation to medical and dental students of Moi University School of Medicine


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Interpretation of Laboratory Toxicology Report:

Interpretation of Laboratory Toxicology Report Dr. Willis Ochieng Toxicologist 11/08/2014 1

Toxicology Laboratory Report:

Report MUST specify-- Name of the deceased , if known Investigation officer or the doctor handling the case and Case or laboratory number whichever is applicable Specimens tested Poisons detected in each specimen and measured concentrations Poisons or drugs which were not found , if they were named in the request Drug or poison detected, but not confirmed Any information about the specimens , such as the date and time of collection of ante-mortem blood Any unusual condition of a specimen Indicateion of where in the body the blood specimen was obtained Report better presented in a tabular form The interpretation should be based on the raised questions the toxicology investigation was required to answer Investigative Questions. What was taken, when and how? Was it a drug or a chemical?  If it was a drug or a mixture of drugs, was it sufficient to cause poisoning?  What were the symptoms or toxic effects?  Does the evidence suggest that the exposure was for therapeutic, suicidal or homicidal purposes?  Was the deceased intoxicated at the time of the incident that caused death?  Is there any alternative explanation for the findings? Toxicology Laboratory Report 11/08/2014 2

Toxicology Laboratory Report Reliability of reported data :

It should be obvious that the interpretation of any toxicology test result will not be more reliable than the analytical result itself . To avoid these interpretative problems, some laboratories have come out with tables of drug concentrations encountered in clinical, toxicological and forensic cases . The interpreter must be satisfied that the analysis is sufficiently accurate for the purpose , or at least know the limitations of the testing by asking the following questions- Was the standard material used to prepare the calibrators pure and correctly identified Was the calibration properly prepared and valid in the range where the specimens were measured? Was the assay sufficiently specific? Could endogenous substances or other drugs or metabolites have interfered with analysis of the specimen, either by obscuring the target poison or increasing the apparent concentration? Although it is practically impossible to know the "absolute" or true concentration of poison in a post-mortem specimen, the degree of confidence increases with the specificity of the analysis , with replication, or in some cases by applying multiple analytical methods of different physical or chemical principle. It is strongly suggested that toxicologists and the sampling doctors should not rely on a toxicology result from a single specimen in fatal intoxication . Such results can be misleading, because of the post-mortem changes that can occur Toxicology Laboratory Report Reliability of reported data 11/08/2014 3

Toxicology Laboratory Report Interpretation of concentration Ratios :

Stomach/Blood Poison in blood/gastric contents Blood/Urine Parent poison/Metabolite Blood/Liver Parent poison/Metabolite Blood/Tissue Tissue poison/metabolites Bile/Urine Parent poison/metabolite Toxicology Laboratory Report Interpretation of concentration Ratios 11/08/2014 4

Toxicology Laboratory Report Post-mortem Kinetics Factors :

  Cessation of active cellular processes and the rapid fall in blood and tissue pH which occurs after death will lead to changes in the conformation of proteins The consequence is the release of poison from protein bound sites, with subsequent diffusion into interstitial fluid, through the capillaries and into the larger blood vessels Since this process appears to start within an hour or so of death, decomposition or putrefaction per se is not likely to play a role in the early stages . Changes in the major organs can also occur by diffusion For example, concentration of poison in one organ can decrease in favour of another When bodies are in a supine position basic poisons in the lungs diffuse rapidly post-mortem into the left cardiac chambers via the pulmonary venous blood rather than simply diffusing across concentration gradients In the past when large tissues were sampled, homogenised, local increases were averaged out Today, only small amount of tissues are analysed which could lead to a gross overestimation of the amount of drug in the organ if the sampled tissue was taken close to the stomach An apparent volume of distribution of more than 3-4 L/kg is a good predictor that a drug is liable to undergo post-mortem redistribution with significant increments in blood levels. Toxicology Laboratory Report Post-mortem Kinetics Factors 11/08/2014 5

Toxicology Laboratory Report Post-mortem Redistribution Factors :

At peri -mortem, the only driving force behind the poison biotranslocation is the concentration gradient . A very important factor to be considered when interprating poison levels in specimens Post-mortem redistribution is likely to be most marked for poisons that are highly protein bound, but particularly those sequestered in the major organs such as the lungs and liver (e.g. Chloroquine ) Post-mortem redistribution is expected to start with the start of the post-mortem changes. The most important quantitative changes in blood drug concentration occur within the first 24 hours or so and are highly site dependent. In general , increases will be greater in blood from central sites Since it is known that many drug concentrations change after death, due to redistribution from the major organs, it is recommended, that post-mortem blood for drug and alcohol analysis be taken from a peripheral site such as the femoral vein In fact it is well established that femoral blood concentrations of many drugs can increase twofold or more after death Femoral blood may contain blood drawn down from the inferior vena cava with a different drug concentration . This is particularly likely to be the case where a large volume of blood has been obtained from a supposedly femoral site Toxicology Laboratory Report Post-mortem Redistribution Factors 11/08/2014 6

Toxicology Laboratory Report Total Body Burden Factor :

  After poison entry into blood and plasma, it may distribute throughout the body . The rate of distribution into each organ is determined principally by blood flow through it and the physicochemical characteristics of the poison The concentration that a poison will achieve in the blood after a toxic exposure will depend largely on its apparent volume of distribution which is governed by its chemistry and kinetics. The bigger the volume of distribution, the more extensive a poison distributes in the biological system The distribution of a toxicant may be complicated by binding to various storage sites in the body such as fat, liver or bone. If these binding sites are not the same as the target sites, then the toxicity of such poisonous substances may not be easily realised Most toxicants can bind plasma proteins especially albumin forming reversible bonds . The bound toxicant is restricted to vascular system due to the high molecular weight of plasma proteins. It is the free poison which is responsible for toxicogenesis and not the bound fraction Lipophilic poisons concentrate in body fats . A poison with a high lipid/water partition co-efficient is stored in fats easily. Obese individuals must be having an extremely high body burden of fat soluble poisons . Such individuals may be exposed to the same stored poisons if there is a sudden rapid release of toxicants from fat depots following starvation or a debilitating disease Most heavy metals have bones as the major site for their storage . This may include non-metallic species like fluoride so long as they have the correct electronic configuration. By virtue of similarities in size and charge, fluoride may readily replace hydroxyl species within the bone matrix. Metals with a related electronic configuration with calcium will replace it from hydroxyapatite lattice structure by an exchange adsorption reaction. Toxicology Laboratory Report Total Body Burden Factor 11/08/2014 7

Toxicology Laboratory Report Estimation Of Body Burden  :

Estimated by the analysis of a poison together with all of its metabolites from different major organs including, where possible, skeletal muscle and then taking into account the organ weights to arrive at a total estimate of the amount in the body In order to improve the reliability, the sample taken must be representative of the remaining organ Since most organs are not homogeneous and the issue of uneven post-mortem diffusion, the sample will have non-homogeneity of concentration While it is easy to know the weight of individual organs , it is very difficult to reliably estimate the total amount of tissue into which most poisons readily distribute While the mass of skeletal muscle can be estimated from medical tables, given a persons height and weight there is no assurance that the concentration of a poison measured in one or two portions of skeletal muscle is representative of that in muscle from all other parts of the body How about the adipose tissues where it is more difficult to obtain representative samples and accurately assay The problem is even greater in a poison or drug with a very big volume of distribution particularly if it was taken for a prolonged period of time Toxicology Laboratory Report Estimation Of Body Burden 11/08/2014 8

Toxicology Laboratory Report Haematoma Factor :

Severe trauma often emanates from an automobile accident which can affect the interpretation of both alcohol and drug concentrations. Toxicological analysis of intracranial haematomas may be useful for-- Determining whether individuals were under the influence of ethanol at the time they were injured Detecting pre-traumatic usage of other drugs and chemicals Medical record should be reviewed thoroughly from a toxicological view point if victims underwent medical treatment prior to death- Because drugs administered for the purpose of medical treatment can disseminate into pre-existing intracranial haematomas, depending on the size of the haematomas Toxicology Laboratory Report Haematoma Factor 11/08/2014 9

Toxicology Laboratory Report Remnants Of Medical Treatment Factor :

Drugs may be used during emergency medical intervention whose blood levels at autopsy may be high In some cases, lidocaine in cases where resuscitation has been unsuccessfully attempted may be 2 to 5 times those normally considered therapeutic when lidocaine is given by i.v . infusion for the treatment of cardiac arryhythmias These could be interpreted as fatal unless all the circumstances are considered. Following intubation, tracheal lidocaine diffuses into surrounding fluids and tissues , attributable to post-mortem acidosis Devices which automatically deliver medication by the parental route will continue the process after death and lead to artificially high blood concentrations post-mortem This can result in extremely high local concentrations of drug which may be misinterpreted as an overdose It would be disastrous if one reported such concentrations as contributory to the process of death without a proper justification Toxicology Laboratory Report Remnants Of Medical Treatment Factor 11/08/2014 10

Toxicology Laboratory Report Additive and Synergistic Toxicity Factor :

This effect should be expected in cases where an individual takes a multiple of drugs at the same time at doses considered therapeutic and dies When interpreting drug concentrations it is important to take into account the sum of the effects of all of the drugs detected Interpretation of blood drug concentrations in these cases has to put into account- Disease which may be present Total amounts of drugs and alcohol In many cases, the affects may simply be addictive Other cases, the effects may be truly synergistic Cases where multiple drugs are present, with or without alcohol, are the most difficult to interpret and rely heavily on the experience of the interpreter and a reliable and complete case history Toxicology Laboratory Report Additive and Synergistic Toxicity Factor 11/08/2014 11

Toxicology Laboratory Report Adverse Reactions Factor :

Death can also follow the administration of therapeutic drugs at the recommended dosages as a result of preponderance of adverse drug toxicity Combinations of a tricyclic antidepressant (TCA) and a monoamine oxidase inhibitor (MAOI) can cause serotonin syndrome Although not always fatal, a serotonin reaction can result in death and might be considered where there is no other reasonable cause of death and especially where there are elevated concentrations of MAOIs and either TCAs or serotonin specific reuptake inhibitors. In drug-drug or adverse reactions, blood concentrations of the drug(s) involved are seldom predictive of the outcome and are often well within the range normally expected from therapeutic doses Toxicology Laboratory Report Adverse Reactions Factor 11/08/2014 12

Toxicology Laboratory Report Biological Instability Factor :

  Many drugs are unstable in biological fluids and may not be detected as parent drugs- Extrapolate toxicity from the levels of its breakdown products which may be innocuous or exhibit very low toxicity Cocaine is probably the most notable example. It is broken down in aqueous solution and in blood or plasma to benzoylecgonine and ethylecgonine , neither of which has much pharmacological activity While cocaine may be stabilised to some extent by the addition of fluoride after the blood is collected, the extent of breakdown between death and autopsy must be considered. The collection and measurement of cocaine in vitreous humour has been attempted to overcome these problems. Toxicology Laboratory Report Biological Instability Factor 11/08/2014 13

Toxicology Laboratory Report Published Values Factor :

Tables of drug concentrations with therapeutic, toxic levels, can serve as a useful reference point Values in tables are derived from serum or plasma data from living patients and may not take into account or state other variables such as post-mortem redistribution, time of survival after intoxication or the presence of other drugs, natural disease or injury Whole blood drug levels is more important to forensic toxicologists than serum or plasma levels Toxicology Laboratory Report Published Values Factor 11/08/2014 14

Toxicology Laboratory Report Morphological Changes Factors :

Except for corrosives and irritants, most poisons do not leave a mark in organs, systems and functions of the body . Structural alterations following intoxication is usually observed without visual evidence of the inciting toxicant Afew chemicals or drugs may bring about alteration of structure with a corresponding altered function This may be exemplified with the antimalarial drug chloroquine which induces phospholipidosis when stored in cells. If this occurs in corneal cells, the alteration is accompanied by visual impairment Some poisons do not bring about a visible functional impairment , cause a reasonable morphological damage Seen is in cases or situations where the target organs functional reserve has not been exceeded despite some toxicity The most difficult to interpret are seen in situations where functional impairment occurs but without morphological abnormality and sometime without the detection of an exogenous poison This is often observed in body systems that have highly specialised physiological functions like cardiovascular and central nervous system where exposure to exogenous or sudden upsurge of endogenous neurotransmitter may have a dramatic effect on the function of the system without any observable morphological alterations Toxicology Laboratory Report Morphological Changes Factors 11/08/2014 15

The End:

The End 11/08/2014 16

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