Kratom: History, pharmacology, current user trends, adverse health effects and potential benefits.

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting.

The 2021 Core Content of Medical Toxicology.

The Medical Toxicology Subboard approved modifications to the Core Content of Medical Toxicology in March 2021. The document outlines the areas of knowledge considered essential for the practice of medical toxicology. The Core Content provides the organizational framework for the development of the Medical Toxicology Certification and Cognitive Expertise Examinations and serves as a template for the development of curricula for medical toxicology fellowship training programs.

Nicotine Content from Cigarettes Submerged in Soda.

INTRODUCTION: Cigarettes and other tobacco products may be extinguished by submersion in liquids in beverage cans or bottles. Cases of nicotine poisoning in children have been reported following ingestion of such liquids. The aim of this study is to analyze the variability of nicotine concentrations with respect to number of cigarettes immersed and the duration of immersion in a soda can METHODS: One unsmoked cigarette was immersed in a cola containing soda can. Three separate samples of the mixture were obtained at different intervals of time post immersion up to 1 week. At the same time, a set of four cola cans were immersed with an increasing number of unsmoked cigarettes and samples obtained. All the samples were then analyzed for nicotine concentrations using liquid chromatography-mass spectrometry. RESULTS: The mean concentration of nicotine measured over the course of 6 hours from one full cigarette in 55 ml of a cola beverage was 0.48 mg/ml. Nicotine concentrations steadily increased in the first 6 hours following submersion, after which, the levels plateaued (r = 0.530, n = 18, p = 0.024). There was a strong positive correlation between nicotine concentrations and the number of cigarettes (r = 0.967, n = 12, p = 3e-7). CONCLUSIONS: The mean concentration of nicotine measured over the course of 6 hours from one immersed cigarette can be potentially toxic especially to children. Nicotine concentrations are positively correlated with the number of cigarettes and time of immersion.

Opioid Toxidrome Following Grapefruit Juice Consumption in the Setting of Methadone Maintenance.

BACKGROUND: Methadone is a synthetic mu-opioid receptor agonist used in the treatment of chronic pain and opioid dependence. Methadone is metabolized by several cytochrome P450 isoenzymes; primarily CYP3A4, CYP2B6, and CYP2D6 before renal and fecal elimination. Exposure to substances like grapefruit juice, that inhibit these isoenzymes may result in increased blood levels of methadone, and thus may manifest clinically as unexpected opioid toxicity. CASE: A 51-year-old male was found unresponsive. He was hypoxic and bradypneic with pinpoint pupils. Multiple boluses followed by infusion of naloxone were required before improvement of respiratory status. Upon awakening, the patient reported participating in an opioid treatment program where he is administered 90 mg of oral methadone daily and denied any other substance use. On further questioning, he admitted to drinking grapefruit juice (estimated to be approximately 500 mL/day) every day for 3 consecutive days before presentation. The patient was discharged home after being counseled to stop drinking grapefruit juice. DISCUSSION: Grapefruit juice is known to be an inhibitor of the CYP3A4 isoenzyme. Various studies demonstrate that through CYP3A4 inhibition, grapefruit juice increases serum levels of opioids, such as methadone, though no clinically significant effects have been reported. CONCLUSIONS: Grapefruit juice inhibits the metabolism of methadone, raising its serum levels. To our knowledge, this is the first reported case in which the interaction between grapefruit juice and methadone was significant enough to cause an opioid toxidrome. It is, therefore, recommended that opioid treatment programs (OTPs) advise patients about this interaction before administering methadone.

Regeneration of a Pediatric Alveolar Cleft Model Using Three-Dimensionally Printed Bioceramic Scaffolds and Osteogenic Agents: Comparison of Dipyridamole and rhBMP-2.

BACKGROUND: Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds. METHODS: Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 µm of dipyridamole (n = 6), 10,000 µm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test. RESULTS: Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-µm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-µm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 µm versus 10,000 µm dipyridamole; p = 0.104), and rhBMP-2-coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 µm dipyridamole, and p = 0.938 versus 10,000 µm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone. CONCLUSION: Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.

Gadolinium Aspiration Following Inadvertent Endotracheal Tube Cuff Injection in a Pediatric Patient.

INTRODUCTION: Gadolinium-based contrast agents (GBCA) are frequently used for MRI contrast studies. We report a case of pulmonary aspiration secondary to inadvertent GBCA injection. CASE REPORT: A 12-year-old female with a past medical history significant for mitochondrial disorder, bronchial asthma, autism, recurrent urinary tract infection, epilepsy, developmental delay, dysautonomia, and thrombocytopenia was scheduled for a contrast-enhanced MRI study using gadoterate meglumine for urinary incontinence. The patient was sedated and intubated in preparation for the study, during which 10 mL of gadoterate meglumine was inadvertently injected into the endotracheal tube cuff pilot line instead of intravenously. The patient remained intubated and was admitted to the intensive care unit with continuous monitoring for signs of pulmonary injury or gadolinium toxicity. She was successfully extubated approximately 24 hours later without complication. DISCUSSION: A variety of adverse effects attributable to parenteral GBCA exposure have been reported ranging from mild irritation to life-threatening anaphylaxis. Gadolinium deposition and storage have been implicated in a number of those adverse effects and multiple treatments modalities have been suggested, but no scientifically guided management exists. CONCLUSION: This case of pulmonary aspiration secondary to inadvertent GBCA injection in a pediatric patient demonstrated no acute  side effects or complications within the first 24 hours. With the wide range of adverse effects attributed to gadolinium use in the medical literature, it is difficult to predict potential future adverse effects.

The implementation of medical monitoring programs following potentially hazardous exposures: a medico-legal perspective.

CONTEXT: Clinical toxicologists may be called upon to determine the appropriateness of medical monitoring following documented or purported exposures to toxicants in the occupational, environmental, and medical settings. METHODS: We searched the MEDLINE database using the Ovid® search engine for the following terms cross-referenced to the MeSH database: ("occupational exposures" OR "environmental exposures") AND ("physiologic monitoring" OR "population surveillance"). The titles and abstracts of the resulted articles were reviewed for relevance. We expanded our search to include non-peer-reviewed publications and gray literature and resources using the same terms as utilized in the MEDLINE search. There were a total of 48 relevant peer-reviewed and non-peer-reviewed publications. Publications excluded contained no information relevant to medical monitoring following potentially harmful toxicologic exposures, discussed only worker screening/surveillance and/or population biomonitoring, contained redundant information, or were superseded by more recent information. Approaches to medical monitoring: A consensus exists in the peer-reviewed medical literature, legal literature, and government publications that for medical monitoring to be a beneficial public health activity, careful consideration must be given to potential benefits and harms of the program. Characteristics of the exposure, the adverse human health effect, the screening test, and the natural history of the disease are important in determining whether an exposed population will reap a net benefit or harm from a proposed monitoring program. Broader interpretations of medical monitoring: Some have argued that medical monitoring programs should not be limited to exposure-related outcomes but should duplicate general preventive medicine efforts to improve public health outcomes although an overall reduction of morbidity, mortality and disability by modifying correctable risk factors and disease conditions. This broader approach is inconsistent with the targeted approach advocated by the Agency for Toxic Substances and Disease Registry and the United States Preventive Services Task Force and the bulk of the peer-reviewed medical literature. Medical monitoring in legal contexts: Numerous medical monitoring actions have been litigated. Legal rationales for allowing medical monitoring claims often incorporate some of the scientific criteria for the appropriateness of monitoring programs. In the majority of cases in which plaintiffs were awarded medical monitoring relief, plaintiffs were required to demonstrate both that the condition for which medical monitoring was sought could be detected early, and that early detection and treatment will improve morbidity and mortality. However, the treatment of medical monitoring claims varies significantly depending upon jurisdiction. Examples of large-scale, comprehensive medical monitoring programs: Large-scale, comprehensive medical monitoring programs have been implemented, such as the Fernald Medical Monitoring Program and the World Trade Center Health Program, both of which exceeded the scope of medical monitoring typically recommended in the peer-reviewed medical literature and the courts. The Fernald program sought to prevent death and disability due to non-exposure-related conditions in a manner similar to general preventive medicine. The World Trade Center Health Program provides comprehensive medical care for World Trade Center responders and may be viewed as a large-scale, federally--funded research effort, which distinguishes it from medical monitoring in a medico-legal context. Synthesis of public health approaches to medical monitoring: Medical monitoring may be indicated following a hazardous exposure in limited circumstances. General causation for a specific adverse health effect must be either established by scientific consensus through a formal causal analysis using a framework such as the Bradford-Hill criteria. The exposure must be characterized and must be of sufficient severity that the exposed population has a significantly elevated risk of an adverse health effect. Monitoring must result in earlier detection of the condition than would otherwise occur and must confer a benefit in the form of primary, secondary or tertiary prevention. Outcome tables may be of use in describing the potential benefits and harms of a proposed monitoring program. CONCLUSIONS: In the context of litigation, plaintiffs may seek medical monitoring programs after documented or putative exposures. The role of the clinical toxicologist, in this setting, is to evaluate the scientific justifications and medical risks and assist the courts in determining whether monitoring would be expected to result in a net public health benefit.

Urine uranium concentrations and renal function in residents of the United States--2001 to 2010.

CONTEXT: Animal model studies have demonstrated that subchronic oral uranium exposure is associated with renal dysfunction. Little is known about the effects of environmental exposure to uranium in humans. OBJECTIVE: To determine whether environmental exposure to uranium is associated with alterations in renal function among residents of the United States. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2001-2010. Inclusion criteria included the measurement of urine uranium concentration, serum creatinine (sCr), and urine albumin-creatinine ratio. Exclusion criteria included a reported history of diabetes mellitus. Urine uranium concentrations were normalized to urinary creatinine. Respondents with and without detectable urine uranium concentrations were compared using Welch's t-test for urine albumin-creatinine ratio and sCr and using Fisher's exact test for a reported history of renal disease. Regression analysis was performed to assess for an association between urine uranium concentration and urine albumin-creatinine ratio, sCr, or a reported history of renal disease. RESULTS: Uranium was detectable in the urine of 74.1% (n = 9025) of respondents. Urine albumin-creatinine ratio was significantly greater in respondents with detectable urine uranium concentrations (mean 4.84 ± 45.8 mg/g) compared to respondents without detectable urine uranium concentrations (mean 0.77 ± 3.7 mg/g) (p < 0.001). There was no significant difference between the groups with respect to sCr or a reported history of renal disease. Regression analysis did not show a statistically significant association between urine uranium concentration and urine albumin-creatinine ratio (p = 0.45), sCr (p = 0.71), or a reported history of renal disease (p = 0.05). CONCLUSIONS: In this study, a high proportion of the U.S. population had exposure to uranium. We demonstrated an association between detectable urine uranium concentrations and microalbuminuria in residents of the United States but no association with clinical renal disease.

Change in perceived risk associated with marijuana use in the United States from 2002 to 2012.

CONTEXT: The role of a dynamic legal, medical, and social setting in affecting the perceived risk associated with smoking marijuana has not been well studied. We sought to determine whether there has been a change in the perceived risk associated with marijuana use over time. METHODS: A cross-sectional study was conducted using the 2002-2012 National Survey on Drug Use and Health. Respondents were asked to classify the risk of smoking marijuana. Regression analysis and the Mann-Whitney U test were used to analyze the data. RESULTS: A total of 614579 respondents were identified. Between 2002 and 2012, the percent of respondents who characterized regular marijuana use as being associated with "great risk" decreased from 51.3% to 40.3%, while the percent of respondents who characterized it as being associated with "no risk" increased from 5.7% to 11.7%. The percent of respondents who characterized occasional use as "great risk" decreased from 38.2% to 30.7%, while the percent of respondents who characterized it as "no risk" increased from 10% to 16.3%. There was a significant negative temporal trend in the perceived risk for both occasional and regular use of marijuana from 2002 to 2012 after controlling for age and gender (p < 0.001 for both). Increasing age was significantly associated with increased perceived risk for both occasional and regular marijuana use (p < 0.001). Males have a significantly lower perceived risk for regular marijuana use as compared with females (p < 0.001). Individuals who used marijuana during the preceding month reported a lower risk perception in both regular and occasional use. CONCLUSION: Between 2002 and 2012, there was a significant decrease in the perceived risk associated with occasional and regular marijuana use. Younger age, male gender, and past month use were also associated with decreased perceived risk.

Metal fume fever and polymer fume fever.

INTRODUCTION: Inhalational exposure to metal-containing fumes generated by welding and related processes may result in the development of the clinical syndrome known as "metal fume fever." Polymer fume fever is a separate and distinct but related disorder that has been associated with inhalational exposure to specific fluorinated polymer products, such as polytetrafluoroethylene or Teflon(®). We undertook a review of the peer-reviewed medical literature as it relates to these two disease entities in order to describe their epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, prevention, and prognosis. METHODOLOGY: We performed a search of the PubMed ( www.pubmed.com ) and Ovid MEDLINE (ovidsp.tx.ovid.com) databases for keywords "metal fume fever," "polymer fume fever," and "fume fever," covering the period 1946 to September 2014, which resulted in a total of 141 citations. Limiting the search to articles published in the English language yielded 115 citations. These 115 articles were manually reviewed for relevance. In addition, the reference lists in each article retrieved were reviewed for additional relevant references. This left 48 relevant citations. EPIDEMIOLOGY: Metal fume fever occurs most commonly as an occupational disease in individuals who perform welding and other metal-joining activities for a living. It is estimated that 1,500-2,500 cases of metal fume fever occur annually in the United States. Polymer fume fever was initially identified as an occupational disease but increased regulations have resulted in decreased incidence in the occupational setting. Overheating of Teflon(®)-coated cookware is one of the more common mechanisms for exposure. PATHOPHYSIOLOGY: While the precise pathophysiology associated with the development of metal fume fever is yet to be elucidated, suggested pathophysiologic mechanisms include pro-inflammatory cytokine release, neutrophil activation, and oxygen radical formation. The pathophysiologic mechanism for polymer fume fever has not been definitively elucidated but may involve similar mechanisms to those proposed for metal fume fever. CLINICAL PRESENTATION: Metal fume fever typically presents with generally non-specific complaints including influenza-like symptoms, fever, shaking chills, arthalgias, myalgias, headache, and malaise. Onset of symptoms typically occurs 4-10 h following the exposure to metal-containing fumes. While metal fume fever is typically benign and self-limited, severe cases of the disease have been reported. In patients with ongoing metal fume exposure over the course of a workweek, tachyphylaxis occurs resulting in improvement in symptoms over the course of the workweek and maximal symptoms occurring after an exposure-free period such as a weekend. The clinical presentation of polymer fume fever is indistinguishable from metal fume fever, with an exposure history being necessary to distinguish the two entities. DIAGNOSIS: Chest radiographs are typically normal in cases of metal fume fever and polymer fume fever; however, mild vascular congestion may be demonstrated and severe cases may feature diffuse patchy infiltrates. Laboratory studies are typically not necessary but may demonstrate leukocytosis with leftward shift or an elevated erythrocyte sedimentation rate. TREATMENT: The primary treatment for both metal fume fever and polymer fume fever is supportive and directed at symptom relief. Oral hydration, rest, and the use of antipyretics and anti-inflammatory medications (e.g., non-steroidal anti-inflammatory drugs and aspirin) are recommended. A careful workplace exposure assessment analysis conducted by an occupational medicine specialist or clinical toxicologist in concert with a qualified industrial hygienist should be performed. PREVENTION: A careful workplace exposure assessment including measurement of ambient zinc and other metal (e.g., chrome, nickel, copper and manganese) fume concentrations or concentrations of fluorocarbon polymer decomposition products at different locations within the workplace should be performed. PROGNOSIS: Metal fume fever is typically a benign and self-limited disease entity that resolves over 12-48 h following cessation of exposure. CONCLUSIONS: Metal and polymer fume fevers generally follow a benign course with spontaneous resolution of symptoms, though both have the potential to be serious, especially in those with significant preexisting cardiorespiratory disease.

Effect of single-dose Ginkgo biloba and Panax ginseng on driving performance.

CONTEXT: Panax ginseng and Gingko biloba are commonly used herbal supplements in the United States that have been reported to increase alertness and cognitive function. OBJECTIVE: The objective of this study was to investigate the effects of these specific herbals on driving performance. MATERIALS AND METHODS: 30 volunteers were tested using the STISIM3® Driving Simulator (Systems Technology Inc., Hawthorne, CA, USA) in this double-blind, placebo-controlled study. The subjects were randomized into 3 groups of 10 subjects per group. After 10-min of simulated driving, subjects received either ginseng (1200 mg), Gingko (240 mg), or placebo administered orally. The test herbals and placebo were randomized and administered by a research assistant outside of the study to maintain blinding. One hour following administration of the herbals or placebo, the subjects completed an additional 10-min of simulated driving. Standard driving parameters were studied including reaction time, standard deviation of lateral positioning, and divided attention. Data collected for the divided attention parameter included time to response and number of correct responses. The data was analyzed with repeated-measures analysis of variance (ANOVA) and Kruskal-Wallis test using SPSS 22 (IBM, Armonk, NY, USA). RESULTS: There was no difference in reaction time or standard deviation of lateral positioning for both the ginseng and Ginkgo arms. For the divided attention parameter, the response time in the Ginkgo arm decreased from 2.9 to 2.5 s. The ginseng arm also decreased from 3.2 to 2.4 s. None of these values were statistically significant when between group differences were analyzed. DISCUSSION AND CONCLUSION: The data suggests there was no statistically significant difference between ginseng, Ginkgo or placebo on driving performance. We postulate this is due to the relatively small numbers in our study. Further study with a larger sample size may be needed in order to elucidate more fully the effects of Ginkgo and ginseng on driving ability.

K2--not the spice of life; synthetic cannabinoids and ST elevation myocardial infarction: a case report.

INTRODUCTION: The adverse effects of synthetic cannabinoids are not well-described nor have they been thoroughly studied. CASE REPORT: A 16-year-old male with a past medical history of asthma and attention deficit hyperactivity disorder (ADHD) presented to the emergency department (ED) complaining of 24 h of substernal pressure associated with dyspnea, nausea, and vomiting. He reported smoking tobacco cigarettes daily and occasional marijuana use but denied recent use of marijuana. The initial electrocardiogram (EKG) revealed ST-segment elevations in leads II, III, AVF, and V4-V6. The initial troponin level was reported as 1.47 ng/mL, and the initial creatine kinase MB (CKMB) level was 17.5 ng/mL. The patient admitted to smoking "K2" 60-90 min prior to the onset of symptoms. The patient manifested persistent ST elevations with a peak troponin of 8.29 ng/mL. The urine drug immunoassay was positive for benzodiazepines and opiates. Cardiac catheterization revealed normal coronary arteries, no wall motion abnormalities, and normal systolic function. DISCUSSION: Synthetic cannabinoids may have significant potential adverse effects. Chest pain due to myocardial ischemia is rare in adolescents. When evaluating patients with chest pain, it is important to elicit a detailed drug history, specifically inquiring about synthetic cannabinoid use. Urine drug immunoassays may be unreliable and in this case did not detect synthetic cannabinoids.

Phenol Toxicity Following Cutaneous Exposure to Creolin®: A Case Report.

INTRODUCTION: Phenol is a caustic that may cause cutaneous or gastrointestinal burns depending on the route of exposure. Significant absorption may result in systemic toxicity. We present a case of topical phenol exposure resulting in cutaneous burns and systemic phenol toxicity. CASE REPORT: A 9-year-old girl was exposed to Creolin(®), a general-purpose disinfectant containing phenol, when her mother applied this product to her head and upper torso. The patient required endotracheal intubation due to depressed mental status; she had cutaneous erythema in the distribution of contact with the cleanser. An initial EKG revealed sinus tachycardia with brief runs of monomorphic ventricular tachycardia. On hospital day (HD) 1, the area of erythema extended to both upper extremities and hyperpigmentation developed over the affected areas, which continued to darken during the hospital course. The patient was extubated late on HD 1. On HD 2, the patient's urine was noted to be a dark green color that resolved later that day. On HD 3, areas of desquamation and decreased sensation developed in skin areas of maximal contact with the cleanser. The patient developed a mild transaminitis with peak AST and ALT levels of 84 units/l and 99 units/l, respectively. The patient was discharged to home on HD 4. DISCUSSION: Our patient presented with signs of cutaneous and systemic phenol toxicity characterized by dermal burns, depressed mental status, cardiac dysrhythmias, and elevated hepatic transaminases. Phenol exposure may cause systemic toxicity following limited dermal exposure.

The perception of odor is not a surrogate marker for chemical exposure: a review of factors influencing human odor perception.

CONTEXT: Clinical toxicologists perform risk assessments and clinical evaluations for patients with potential exposure to airborne toxicants in which the patient's self-reported perception of odor may be the only indicator that an exposure may have taken place. OBJECTIVE: To review the factors that may affect the human ability to perceive chemical odors and relate those odors to specific chemical exposures. METHODS: The medical literature, from 1950 through 2012, was searched using the OVID database and the PUBMED database. The searches returned 238 articles, of which 113 involved human studies and were published in the English language. Of these 113 articles, 40 articles discussed odor issues and thus were chosen as specifically relevant to the topic. Bibliographies of all articles were also searched for other relevant references and this found six additional articles, making a total of 46. FACTORS THAT MAY AFFECT OLFACTION AND THE ABILITY TO PERCEIVE ODOR: Genetic/population: Ethnic background is associated with widely differing odor detection abilities and thresholds. A significant genetic influence for the ability to smell and perceive odor has been reported. Gender: Women are superior to men in their ability to identify odors. Age. Increasing age is correlated with higher odor detection thresholds. Medical conditions: A variety of medical conditions have been associated with deficits in olfaction, including diseases of the nose and sinuses, multiple sclerosis, and schizophrenia. Alcoholism and smoking: Abuse of alcohol results in impaired olfactory sense, and smoking tobacco products alters odor detection threshold in a dose-related manner. Occupational and environmental factors: Repeated inhalation of any chemical results in olfactory fatigue over relatively short time frames that leads to a decreased ability to accurately detect and identify an odor. Recent exposure to relatively high concentrations of a chemical has been shown to affect sensitivity to that particular odorant, altering subsequent detection thresholds by up to three orders of magnitude. Applicability of proposed odor thresholds: Humans are only able to identify three to four components of complex olfactory mixtures and the odorants present in the mixture affect which individual components are detected. Odorants present in suprathreshold concentrations in a mixture may effectively mask the presence of odorants present in perithreshold concentrations. Self-rating of olfactory function may not correlate with actual olfactory ability. It is even more difficult to accurately determine intensity of an odor in a quantifiable way. For example, under conditions of constant stimulation with hydrogen sulfide, perceptual intensity was reported to decrease exponentially with time of stimulation. Concomitant visual stimulation also affects odor intensity. Some chemicals, such as hydrogen sulfide, may induce reactions in humans related solely to their odor, even when they are present in concentrations substantially lower than those levels usually associated with the development of adverse clinical effects. There is a wealth of literature suggesting that the intensity of perceived odor, the degree of irritation, and the reported health effects of exposure to an odorant chemical are affected by psychological state and bias. Multiple theories have been proposed to explain the cognitive basis for perceived illness in association with the perception of odor. The concept of odor has been reported to be intrinsically and cognitively associated with illness rather than with health. Assigning negative bias to an odor prior to an exposure results in the reporting of significantly more health-related symptoms following exposure. This suggests that those symptoms are not mediated by the odor directly, but rather by an individual's cognitive associations between odor and health. CONCLUSIONS: Attempts to verify exposure intensity based on the report of a perceived odor is unreliable and has no useful application in legitimate exposure assessment paradigms. Detection of an odor does not imply a medically significant exposure to a toxicant and, due to subject bias and the difficulty of detecting individual odorants in mixtures, may not constitute an exposure to the purported substance.