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Ultimately, the toxicologist’s role in forensic interpretive toxicology is to correlate analytical findings or theory to an adverse outcome. Although explanations abound, both in concept and practice, plausible explanations are often few. It is rare that findings can simply be taken at face value. For example, it is common for identical findings in two different cases to have two completely distinct interpretations, which should not be surprising or disconcerting. Toxicology has been described as both science and art, with the interpretive aspect based in science, knowledge, and experience.20 Many of the following factors need to be considered in rendering rational opinions.
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It is not uncommon for individuals to render toxicologic opinions without careful review of the analytical data that help form the basis of the opinions. Simple acceptance of reported results can be a fundamental flaw in medicolegal interpretations. It is helpful to review all available information that led to a reported result before interpretation. Table 7–5 lists some of the important facets of analytical data review that can lead to incorrectly reported results. Although there is no expectation that the toxicologist be an expert in analytical chemistry, familiarity with the key elements that can lead to false-positive, false-negative, or poorly quantified findings should become part of the review process. Errors ranging from the wrong patient number on the analytical data to poor control and calibration of an analytical run to poorly integrated chromatographic peaks are all examples of errors that can invalidate any given finding.
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Postmortem Redistribuiton
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There are many factors related to postmortem changes that complicate the interpretation of well-performed toxicologic test results.16,17,38,61 Many of these factors are discussed in Chap. 34. However, the importance of PMR, a long-established principle in forensic toxicology, cannot be ignored or underestimated. Although recognized in the early 1980s, Prouty and Anderson authored the first codified report of this phenomenon in 1990.54 Succinctly, PMR is the term given to changes in site-specific xenobiotic concentrations after death.50 These xenobiotic movements postmortem generally result in elevated concentrations in common collection sites such as heart blood. The elevation for some substances can be dramatic, giving the appearance of overdose when no such conclusion is supported by other evidence, including analysis of sites of blood collection where PMR may occur to a lesser degree, such as femoral blood. Although instructed to do otherwise, many pathologists still collect heart blood as a sole source of postmortem blood. In attempting to assist in such situations, investigators often publish ratios of heart blood concentrations to femoral blood concentrations over a series of cases from a given laboratory. The common observation is a widespread range of values often encompassing three- to fivefold or greater differences in magnitude.8 The use of such ratios to convert a heart blood concentration to a femoral blood concentration, and by further analogy to a premortem circulating blood concentration, should not be performed. The greatest use of such ratios is to give an idea of the likelihood of PMR for any given xenobiotic based on the mean and range of ratios.43 Because it cannot be predicted if PMR occurred in any given case and if so to what degree and over what time period, such calculations have no basis for antemortem blood concentration determination. Another confounder to the use of ratios is the possibility that site-specific differences are not due to PMR but merely a reflection of incomplete distribution before death.17 It is unclear how many of the reported ratios of heart blood to femoral blood actually reflect this process as opposed to true PMR. The proposed mechanisms and influencing factors resulting in PMR are varied and are listed in Table 7–6. It is most likely a combination of factors that lead to PMR in any given case. Interestingly, as noted earlier, PMR is also reported to take place in femoral blood; thus, it should not be taken at face value that any postmortem blood concentration accurately reflects that circulating at and around the time of death.
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At one time it was believed that PMR was associated with basic xenobiotics with a large volume of distribution. Seemingly, however, most xenobiotics, including acidic and neutral xenobiotics, undergoes PMR. Furthermore, PMR occurs for xenobiotics with wide-ranging volumes of distribution. Still other xenobiotics that would be predicted to undergo PMR have experimental evidence to the contrary.50 Thus, a priori predictions of PMR for any given xenobiotic without experimental evidence should explicitly state the caveats associated with such a conclusion. It must be stated, however, that PMR does not preclude the interpretation of findings for cause of death determination because the findings represent only one piece of data in a potential myriad of other relevant information.
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Another similarly related phenomenon is postmortem diffusion of xenobiotics. In this situation, diffusion of xenobiotics from an area of high concentration to that of a lower concentration occurs. This is most noted when the gastric contents contain a substantial amount of a xenobiotic that migrates across the wall of the stomach into neighboring tissues and blood sources, such as abdominal aorta and iliac vessels. Additionally, perimortem aspiration of gastric contents can lead to significant esophageal, tracheal, and lung concentrations of a xenobiotic, further facilitating diffusion processes.10,52
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Although most discussions regarding interpretive toxicology tend to focus on blood concentrations of xenobiotics, clearly in both the living and the dead, alternative matrices have become extremely valuable. It should be recognized that there is no perfect specimen to assess exposure or provide analytical findings in support of impairment. In the living, alternative specimens including hair, oral fluid (OF), and breath are useful. Hair gives a longer window of detection than most other easily obtained specimens.62 Analytical precautions, such as rinsing procedures, can be used to minimize some concerns with hair testing.56 The utility of hair should not be underestimated, and despite some of its limitations, it can represent the best suited specimen in some cases, such as drug-facilitated sexual assault, especially when more than 24 to 48 hours passed before specimen collection from the time of event, thus often limiting the value of urine or blood testing.35 In such cases, waiting 1 to 3 months before collecting hair will capture the potential exposure period in growing hair. It is especially useful in children to demonstrate acute versus chronic exposure to xenobiotics.45 Collection of hair should be from the posterior vertex of the head, which can be easily approximated by drawing an imaginary line over the head connecting the tops of both ears and a line from the bridge of the nose to the nape of the neck.11,56 Where the two lines meet in the back of the head provides hair that grows most consistently on the head.34 About a pencil thickness worth of hair should be clipped as closely to scalp as possible.12 The root ends should be identified either by tying with string or wrapping in foil.11 Virtually any other source of hair can be tested as well, such as pubic and axillary hair, although practical reasons and shorter growth rates tend to make such samples less suitable for testing.
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Oral fluid (OF) is gaining ground as a viable specimen type to assess exposure and impairment because obtaining it is noninvasive, and it can be collected at the site of an event, thus eliminating time delays.4 Such delays can result in clearance of a xenobiotic from other specimen types before collection. OF is composed of secretions from the parotid, submaxillary, sublingual, and other smaller glands. Numerous specimen collection devices exist today that circumvent the need to expectorate, which is not a desirable means of specimen collection.48 For the most part, non–protein-bound parent compounds appear in OF, although there are exceptions (eg, benzoylecgonine).13 Factors that affect how much of a xenobiotic gets into OF include pH of the blood and OF, the pKa of the xenobiotic, and the degree of protein binding. In general, basic xenobiotics get into OF easier than acidic xenobiotics.65 OF has been used for therapeutic drug monitoring purposes (eg, theophylline and digoxin).6 Although some correlations between blood concentrations and a number of xenobiotics have been made, it must be remembered that OF is susceptible to contamination from residual drug in the oral cavity, smoked drugs, and passive exposure.4,13 Despite its promise, there is variability in OF concentrations of xenobiotics not only within the same individual but also among individuals based on influencing factors that facilitate or inhibit secretion of a xenobiotic into OF.4 Last, based on the relatively small specimen volumes after OF collection, specialized testing, including tandem mass spectrometry, is often needed to detect the concentrations of xenobiotics present.
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Breath testing for alcohol is a mature subject matter, yet when it comes to impairment, there is a current trend for states to move back to blood alcohol determinations. Legal arguments have been the force behind some of this movement.49 Breath testing for other xenobiotics is still in its fledgling state. Despite this, the future holds promise for the detection of other xenobiotics in breath with the possibility of roadside breath drug-testing devices.3 The major advantage of this specimen is its lack of invasive collection technique and rapid screening capability.
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Alternative matrices from decedents are varied and have included virtually all fluids and tissues (Table 7–4). Practically speaking, however, other than providing qualitative information, for most matrices, there is little data to support utility of a measured concentration to either allow for independent interpretation or correlation to blood concentrations. Although numerous studies exist that suggest such correlations, rarely is there consistency between studies. Even so, situational use of alternative matrices is sometimes warranted (eg, the use of fat or brain to detect volatiles). A specific exception is vitreous humor (vitreous), a specimen that is often extremely valuable postmortem. Vitreous electrolyte measurements provide data that cannot be gleaned from virtually any other specimen type (Table 7–7).7 For most xenobiotics, vitreous concentrations lag behind blood concentrations by about 1 or 2 hours. Thereafter, some correlations have been made between vitreous concentrations and those in blood, with the greatest example being ethanol, where there is an approximately 1:1 correlation when equilibrium is reached. Vitreous represents a relatively pristine specimen during decomposition, embalming, exsanguinations, severe peritoneal trauma, and other less ideal situations.21
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Toxicokinetics and Toxicodynamics
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The basics of toxicokinetics (TK) and toxicodynamics (TD) are covered in Chap. 9. The large and unpredictable degree of interindividual variability places practical limits on the use of TK and TD in postmortem interpretation. These same variations affect the pharmacologic response in living patients. Multiple elements related to TK and TD affect the ability to render interpretive opinions of xenobiotics related to an adverse outcome (Table 7–8). Many of these issues are covered elsewhere; however, the use of pharmaco- and toxicokinetic equations warrants special attention.
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Toxicologic emergencies and overdoses often lead to derangement of normal physiological functions. Distortions, especially in liver and kidney function, can significantly alter normal TK parameters.59,63 Coupled with pharmacogenetics, drug–drug or drug–xenobiotic interactions, pathophysiology, and other significant factors, the use of routine TK equations can lead to grossly under- or overestimates of a specific measured value. Nevertheless, in a living patient, TK equations can be useful to estimate certain parameters (eg, dose and, in part, form the basis of such useful tools as nomograms). Postmortem, because of PMR and postmortem diffusion alone, the use of TK formulas to predict premortem concentrations or dosing is not generally an acceptable practice. For example, the use of the following formulas will lead to either an absurd dose calculation or an inappropriate estimate of predicted concentration compared with that reported for compounds undergoing significant PMR:14,27
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Nevertheless, such calculations, although ill advised, are routinely performed and can provide grossly misleading information. “Back extrapolating” from a postmortem concentration to some concentration earlier in time using half-life is fraught with the same perils in that the beginning assumption of an unchanged postmortem blood concentration can rarely be made.16 Additionally, it is never known how much of any measured blood concentration resulted from a single or multiple dosing. Despite these issues, the toxicologist may be pressured into providing dosing information or predicting a blood concentration during life. The safest avenue in this respect is not to accede to such pressures because the scientific underpinnings are shaky at best.
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There exist two broad areas of concern with respect to impairment, that from alcohol and that from other xenobiotics. Impairment caused by alcohol has been long studied, and general conclusions are usually reached with some confidence. The same cannot be stated for impairment caused by drugs. Ultimately, conclusions of drug impairment are based on physical examination by a trained clinician, dosing information, length of time taking a medication, co-administered medications, pathophysiology, observed behaviors, measured concentrations in blood or serum or plasma, and any other useful information.32 The use of the term “consistent with” is common in assessing impairment in any given individual and might very well be the best opinion that can be offered. Mitigating factors, including tolerance, single versus multiple dosing, reason for the presence of the substance, timing and route of administration, and pathophysiology, all make firm conclusions difficult, especially when blood findings are the first indication of potential impairment (ie, no visible signs of impairment).28,57 Great care must be exercised in evaluating or predicting impairment from drugs given the implications of such conclusions. There is currently no scientific support for back extrapolation of drug concentrations based on blood findings. It cannot be stressed enough that urine findings should never be used to assess impairment because the predictive value is limited.64 Similar to blood alcohol concentration, many states and countries have developed per se drug laws that presume guilt by the presence of certain drugs or metabolites over some prescribed reportable concentration, even in urine, thus mitigating the need for interpretation in most cases. For example, the presence of carboxy-tetrahydrocannabinol, an inactive metabolite of marijuana, is used to convict drivers of impaired driving; for clarity, this is a legal issue, not a scientific, issue.30,36 Last, tables and texts that list xenobiotics and determined concentrations in blood and other specimens should only be used as a guide for interpretive purposes because every case is unique.