Threshold values in toxicology - useful or not?

In many fields of toxicology, numbers are used as threshold values, e.g. as "acceptable daily intake values" resulting in maximum permissible concentrations in food or in animal feed by using "safety factors"; maximal admissible concentrations of toxic substances in the air at the workplace; cut-off values in analytical toxicology; limit values for biological specimens in the case of driving under the influence of drugs, guidance values for environmental specimens, etc. The philosophy behind these values must be well understood and they should only be applied to real cases by persons with enough toxicological background. The bad use of these numbers in toxicology can have dramatic consequences. Especially in regulatory toxicology their use should be made with great care. Moreover, tremendous improvements in analytical methodology, e.g. the decreasing of the limits of detection for many potentially toxic substances in recent years, should not end up in an overestimation of risks to humans. To avoid these abuses careful interpretations of analytical findings by qualified toxicologists are of paramount importance. The use and abuse of some of these threshold values will be outlined in several applications from analytical toxicology, risk assessment issues, forensic toxicology in post-mortem cases, as well as from the drugs and driving cases. Generally, if threshold values are considered as guidance values and not as the "absolute truth" in toxicology, they may be very useful in the interpretation of toxicology data.     

Toxicology case data reporting system

A computerized system has been organized to serve the toxicology sections of seven R.C.M.P. laboratories across Canada. Scientists may view and retrieve information concerning drugs and drug combinations, blood and liver drug concentrations, etc. from cases of sudden death or impaired driving which were analyzed in the laboratories. This has proven to be a great help in interpreting toxicology case results for the investigator or the courts and also in choosing methodology to be used in analyzing specimens for unusual drugs or poisons.     

Suicidal Drug Overdoses in New Mexico: A 5‐year Retrospective Review

To better understand the changing toxicology trends in suicidal drug overdoses in the setting of an increased national trend of multidrug overdoses, a retrospective review of electronic records from New Mexico's Office of the Medical Investigator database was performed between 2008 and 2012 to assess the drug type and current risk factors in suicide deaths. Information on demographics, circumstances, suicide risk factors, toxicology findings, and death certificates was collected and analyzed. Three hundred and forty‐two suicide cases of suicide overdoses were identified. Decedents were predominantly female (61.8%). Scene investigation revealed risk factors including suicide ideation (47.4%), previous suicide attempts (38%), and suicide note (38%). Psychiatric illness was present in 72% of cases, with depression being the most common illness. Chronic pain was seen in 27.2% of cases. Most deaths were attributed to multiple drugs (76%). Utilizing the toxicology information will assist in creating public awareness and provide a framework to support targeted efforts to attempt to prevent future suicides.     

A rapid method for blood alcohol determination by headspace analysis using an electrochemical detector.

A method for the determination of blood alcohol concentration by headspace analysis using an electrochemical detector is described. A determination can be made within 2 min, and only 0.1 ml of blood is required for each analysis. The detector response was linearly related to ethanol concentrations up to 3.0 mg/ml. The standard deviation of a single determination was +/- 0.014 mg/ml. The accuracy of the method based on comparison with an enzymatic (alcohol dehydrogenase) technique was high, the mean recovery being 102.2% of the attributed concentration. The ease of the operation and fast analysis time make the method ideal for serial determinations, for example during mass screening of biological samples for ethyl alcohol in forensic and toxicology laboratories.     

Toxicological Findings in Fatal Motor Vehicle Collisions in Ontario,Canada: A One‐Year Study

Drug‐impaired driving is a complex area of forensic toxicology due in part to limited data concerning the type of drugs involved and the concentrations detected. This study analyzed toxicological findings in drivers from fatal motor vehicle collisions (FMVCs) in Ontario, Canada, over a one‐year period using a standardized protocol. Of the 229 cases included in the study, 56% were positive for alcohol and/or drugs. After alcohol, cannabis was the most frequently encountered substance (27%), followed by benzodiazepines (17%) and antidepressants (17%). There were differences in drugs detected by age but no marked difference in drugs detected between single and multiple FMVC's. Not all drugs detected were considered impairing either due to drug type, concentration or case history. The findings indicate the importance of comprehensive drug testing in FMVCs and highlight the need to consider a variety of factors, in addition to drug type and concentration, when assessing the role of drugs in driving impairment.     

Screening analysis for medicinal drugs and drugs of abuse in whole blood using ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS)-Toxicological findings in cases of alleged sexual assault

An ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS) method for simultaneous screening of 46 medicinal drugs and drugs of abuse in whole blood was developed and validated. The method includes most of the commonly used and abused drugs such as amphetamines, cocaine, benzodiazepines, and opioids. Chromatographic separation of the targeted drugs was achieved using a Waters ACQUITY UPLC coupled to a Waters Micromass LCT Premier XE time-of-flight mass spectrometer. The total chromatographic run time was 13.5min injection to injection. The estimated method LOQ is in the range of 0.06-27ng/g, which is below the therapeutic levels for each of the drugs analyzed but LSD. The extraction recovery ranged from 6% to 197% with median value 95% and mean value 82%. Matrix effect ranged from 81% suppression to 29% enhancement of the signals compared to signals obtained in the absence of biological matrix. The method was tested on 55 authentic forensic toxicology samples confirming the same positive results as found using the routine analytical procedures as well as some additional compounds. Recently there has been considerable attention paid to drug-facilitated sexual assault and the toxicological findings in these cases. As part of a pilot study to investigate the prevalence of medicinal drugs, drugs of abuse, and alcohol in victims of alleged sexual assault, biological specimens were obtained from 167 victims being examined at the Sexual Assault Center in Aarhus, Denmark. The obtained blood samples were analyzed using the novel screening method supported by additional analyses for e.g. THC and alcohol. 124 victims reported they have been drinking alcohol prior to the assault (74%). Alcohol analyses revealed 59 positive findings (48%). 35 of the cases were found positive for one or more drugs excluding alcohol (21%). 20 of the victims reported they have been subject to a drug-facilitated sexual assault (12%). For the victims suspecting drug-facilitated sexual assault, the toxicological analyses revealed four positive for alcohol and nine victims were positive for one or more drugs, with six of the victims found positive for benzodiazepines or other drugs with sedative effects. It was notable that victims tested positive for medicinal drugs and drugs of abuse as well as victims of alleged drug-facilitated sexual assault in average underwent medical examination later than the whole study population.     

The predictive value of history and scene investigation for toxicology results in a medical examiner population

Medical examiner offices vary in the extent to which they pursue postmortem toxicology. Our office routinely tests decedents for ethanol and drugs of abuse, and we decided to evaluate the usefulness of our practice. We reviewed 1180 medical examiner cases examined in 2002-2003. History and scene investigation indicated that alcohol or drugs of abuse were likely to be detected in 369 cases, yet toxicology testing revealed an intoxicating substance in 589 cases, a prevalence of 50%. Screening for toxicology testing based on investigative findings had a sensitivity of 0.47, a specificity of 0.84, and a positive predictive value of 0.74. Moreover, even in the 811 cases where initial investigation did not suggest substance abuse, toxicology testing revealed at least 1 substance that was pertinent to the subsequent investigation in one third of the cases (260), and the intoxicating substance was sufficiently important to merit inclusion as a cause of death or contributing factor in nearly half of those cases (113). We conclude that investigation alone is ineffective at predicting the presence of intoxicating substances within decedents.     

Suicides by fall from height in Geneva,Switzerland, from 1991 to 2000

Suicides due to fall from height in Geneva from 1991 to 2000 were reviewed. Scene investigations, autopsy findings, psychiatric histories, and toxicology results were examined. There were 197 of these suicides, an incidence of five cases per 100,000 inhabitants per year or one fourth of all suicides in Geneva per year. Autopsies were performed on 33%, the rest had external examinations. Of the victims, 56% were female and 44% were male. The age distribution peaked at 20-29 years in men and 60-69 years in women. Most of the victims jumped from their home, the range of 2 to 7 stories being the most frequent height. Major injury sites, in decreasing frequency, were the thorax, abdomen, skull, vertebrae, pelvis and limbs. Psychiatric illness was reported in 38% of the cases. Toxicological analysis was performed in 25% of the cases and showed that the main drugs present were benzodiazepines, cannabis and antidepressant.     

Drugs WorkBook (DWB): A tool for the analysis of illicit drugs in seized materials

Accurate and reliable analytical measurements are essential when data are to be used to assist the Court in deciding whether or not a drug offence has been committed and therefore about either the innocence or guilt of the accused. The Italian law on drugs demands that compliance with specification limits be assessed on the basis of the actual content of controlled substance contained in seized materials. As a consequence, the role of measurement uncertainty, significant figures and rounding errors becomes critical. In order to assist analysts of forensic toxicology laboratories with illicit drug-related cases, a software tool named Drugs WorkBook (DWB) has been developed. The tool is useful for the quantification of illicit drugs in seized materials along with their measurement uncertainties, the assessment of compliance to specification limits, the printing of comprehensive laboratory reports and the organization of case archives. Other quality control topics, such as control charts, are included. The tool's databases can be edited by the user and maintained up to date. The tool is made freely available to the scientific community.     

Situations of poisoning and analytical toxicology in Japan

Unprecedented poisoning terrorism by use of sarin took place in Japan in 1994 and 1995. On July 25, 1998, a curry poisoning incident in Wakayama occurred resulting in the death of four people and injury of 63 people. Since then, more than 30 imitative poisoning cases have been reported by mass communication within 1 year. In this brief review, we present some details of a series of poisoning cases and measures taken by the Japanese Government and non-government groups. In addition some research projects on analytical toxicology being conducted in our laboratories are also introduced; gas chromatography (GC) with cryogenic oven trapping for volatile organic compounds, and GC/surface ionization organic mass spectrometry for tertiary amino compounds are described especially as new techniques for biological samples.     

The screening and quantitation of diazepam, flurazepam, chloridazepoxide, and their metabolites in blood and plasma by electron-capture gas chromatography and high pressure liquid chromatography

A combined GLC-ECD and HPLC procedure has been developed for the analysis of the most commonly encountered benzodiazepine drugs and has been applied to both plasma and postmortem blood samples. There is no doubt that since their introduction the use of these sensitive analytical methods have resulted in an increase in the incidence of detection of these drugs in both clinical and forensic toxicology cases.     

A Census of Medicolegal Death Investigation in the United States: A Need to Determine the State of our Nation’s Toxicology Laboratories and Their Preparedness for the Current Drug Overdose Epidemic

In 2007, the Bureau of Justice Statistics reported on 2004 data collected from the Census of Medical Examiner and Coroner Offices (CMEC). The CMEC was one of the first comprehensive reports on the state of the medicolegal death investigation system in the United States and included information on administration, expenditure, workload, specialized death investigations, records and evidence retention, and resources. However, the report did not include responses on questions that were related to toxicology such as specimen retention and type of testing. The purpose of this publication is to provide the community with toxicology laboratory-specific responses from nearly 2000 medical examiner and coroner (MEC) offices. Data obtained from a BJS CMEC public use dataset for any remaining information that was not reported in the 2007 BJS report were evaluated specific to the operation of toxicology laboratories within a MEC office or specific to toxicology testing. The CMEC includes information on average operating budget for MEC offices with internal or external toxicology services, budget for toxicology/microbiology services, respondents’ routine uses of toxicology analysis, toxicology specimen retention time, average turnaround times, use of computerized information management systems, and participation in federal data collections. These historical data begin to address the present state of our nation’s toxicology laboratories within the medicolegal death investigation system and their preparedness for the current drug overdose epidemic.     

Emergence of fentanyl-related deaths in Travis County,Texas and surrounding areas: A retrospective review of postmortem fentanyl-related drug toxicities from 2020 to 2022

The opioid epidemic has affected the United States (US) for decades with fentanyl and its analogs accounting for a recent surge in morbidity and mortality. Currently, there is a relative lack of information characterizing fentanyl-related fatalities specifically in the Southern US. A retrospective study was conducted to examine all postmortem fentanyl-related drug toxicities in Travis County, Texas, encompassing Austin (one of the fastest-growing cities in the US), from 2020 to 2022. Fentanyl contributed to 2.6% and 12.2% of deaths submitted for toxicology between 2020 and 2022, respectively, representing a 375% increase in fentanyl-related deaths over this 3-year period (n = 517). Fentanyl-related fatalities primarily occurred in males in their mid-30s. Fentanyl and norfentanyl concentrations ranged from 0.58 to 320 ng/mL and 0.53 to 140 ng/mL with mean (median) concentrations of 17.2 ± 25.0 (11.0) and 5.6 ± 10.9 (2.9) ng/mL, respectively. Polydrug use was present in 88% of cases, with methamphetamine (or other amphetamines) (25%), benzodiazepines (21%), and cocaine (17%) representing the most frequently identified concurrent substances. Co-positivity rates of various drugs and drug classes widely varied over time. Scene investigations reported illicit powder(s) (n = 141) and/or illicit pill(s) (n = 154) in 48% (n = 247) of fentanyl-related deaths. Illicit oxycodone (44%, n = 67) and illicit “Xanax” (38%, n = 59) pills were frequently reported on scene; however, toxicology only identified oxycodone and alprazolam in 2 and 24 of these cases, respectively. The results of this study provide a better understanding of the fentanyl epidemic in this region creating an opportunity to promote increased awareness, shift focus to harm reduction, and aid in minimizing public health risks.     

Acidic and neutral drugs screen in blood with quantitation using microbore high-performance liquid chromatography–diode array detection and capillary gas chromatography–flame ionization detection

Blood previously acidified with aqueous saturated ammonium chloride solution was extracted with ethyl acetate. The dried extract was subjected to acetonitrile–hexane partition. The acetonitrile portion was analysed for the presence of acidic and neutral drugs by HPLC–DAD (200 mm×2.1 mm I.D. microbore ODS-Hypersil column) and GC–FID (25 m narrow-bore×0.25 mm I.D. HP-5 column with 0.33 μm film thickness). The protocol was found to be suitable for both clinical toxicology (including emergency toxicology) and postmortem toxicology. At least 66 drugs of interest were unequivocally identified by RRTs (HPLC) and UV spectra (DAD) match while another 12 were unequivocally identified by double RRTs match (HPLC and GC). Quantitation was facilitated by incorporating calibration blood standards in each assay batch. The five drugs most commonly encountered in clinical blood specimens (1150 cases) were: paracetamol (47.4% of the cases); chlormezanone (6.6%), theophylline (1.74%), naproxen (1.65%) and mefenamic acid (1.56%). The following drugs were detected in toxicologically significant quantities in postmortem blood specimens (245 cases): phenobarbitone (1.22% of the cases), naproxen (0.82%), chlormezanone (0.82%), theophylline (0.82%), carbamazepine (0.41%) and paracetamol (0.41%).     

The FAA's postmortem forensic toxicology self-evaluated proficiency test program: the first seven years

Existing proficiency-testing (PT) programs do not address the complexity of postmortem forensic toxicology. These programs do not include decomposed samples and solid tissues. Therefore, the Federal Aviation Administration in July 1991 started such a needed PT program. This program is used to: (i) professionally develop and maintain technical currency on a voluntary, interlaboratory, and self-evaluation basis, and (ii) quantifiably assess methods in the absence and presence of interfering substances. There are currently about 30 laboratories in the program. Functioning under various governmental/non-governmental agencies and academic institutions, these laboratories represent a broad cross-section of the country. PT samples are distributed quarterly, and result summaries are sent to the participants, while maintaining their anonymity. Since the inception of the program, 28 PT samples encompassing whole blood, plasma, urine, kidney, or liver, with (or without) drugs, metabolites, and common chemicals (nicotine, caffeine, beta-phenylethylamine, etc.) have been analyzed by the participants. Analytical findings were generally consistent with the anticipated values, but they were dependent on the nature and conditions of the specimens and types of the added analytes. Some incidences of false positives of concern were noted, as well. This PT program is one of the few programs recommended by the American Board of Forensic Toxicology in which laboratories may participate for their accreditation by the Board. It is anticipated that this PT program will continue to play a critical part in supporting the quality assurance/quality control (QA/QC) component of forensic toxicology, thereby enhancing operational performance.     

Report of Increasing Overdose Deaths that include Acetyl Fentanyl in Multiple Counties of the Southwestern Region of the Commonwealth of Pennsylvania in 2015–2016

Acetyl fentanyl is a Schedule I controlled synthetic opioid that is becoming an increasingly detected “designer drug.” Routine drug screening procedures in local forensic toxicology laboratories identified a total of 41 overdose deaths associated with acetyl fentanyl within multiple counties of the southwestern region of the state of Pennsylvania. The range, median, mean, and standard deviation of blood acetyl fentanyl concentrations for these 41 cases were 0.13–2100 ng/mL, 11 ng/mL, 169.3 ng/mL, and 405.3 ng/mL, respectively. Thirty‐six individuals (88%) had a confirmed history of substance abuse, and all but one case (96%) were ruled multiple drug toxicities. This report characterizes this localized trend of overdose deaths associated with acetyl fentanyl and provides further evidence supporting an alarmingly concentrated opiate and opioid epidemic of both traditional and novel drugs within this region of the United States.     

The use of hair as a toxicological tool in DFC casework

When drugging related offences are cited, most people think of sexual assault. However, the law covers any crime committed whilst the complainant is under the influence of alcohol or drugs i.e. the use of a drug to modify a person's behaviour for criminal gain. The case types encountered include robbery, blackmail and of course sexual offences.Hair analysis for drugs is now well established in Forensic Toxicology. Its use as an analytical tool in workplace testing, post-mortem toxicology and criminal cases is expanding both in the UK and worldwide, and it is now widely accepted as an alternative or complimentary matrix for these cases. This paper will provide a brief overview of hair testing in cases of Drug Facilitated Crime stressing the importance of timely sample collection. Its usefulness in cases of this type will be highlighted through case examples.     

Suffocation using plastic bags: a retrospective study of suicides in Ontario, Canada

One hundred and ten cases of suicidal suffocation using a plastic bag were identified in the files of the Office of the Chief Coroner of Ontario, Canada, between 1993 and 1997. The records were reviewed to determine the demographic characteristics of this group compared with all cases of suicide in Ontario, the scene information, autopsy findings and toxicology results. Most suicides occurred in people over 60 years of age, with older women making up a considerable proportion of cases as compared with other methods of suicide. In 40% of cases the deceased was suffering from a serious illness. Autopsy findings were usually minimal, with facial, conjunctival and visceral petechiae present in a minority of cases. One or more drugs were detected in the blood in 92.6% of cases where toxicologic testing was performed. Benzodiazepines, diphenhydramine and antidepressants were the most common drugs found, with diphenhydramine the most common drug present at an elevated concentration. Information at the scene from "right to die" societies was uncommon. One quarter of decedents took additional measures, besides the use of drugs or alcohol, to ensure the rapidity, certainty or comfort of their death. This study further elucidates the characteristics of this uncommon method of suicide. It emphasizes additional scene findings, such as the presence of dust masks, physical restraints and modification of the plastic bag that may be of use to death investigators in determining the correct manner of death.