Multiple chemical sensitivity: It's time to catch up to the science.

Multiple chemical sensitivity (MCS) is a complex medical condition associated with low dose chemical exposures. MCS is characterized by diverse features and common comorbidities, including fibromyalgia, cough hypersensitivity, asthma, and migraine, and stress/anxiety, with which the syndrome shares numerous neurobiological processes and altered functioning within diverse brain regions. Predictive factors linked to MCS comprise genetic influences, gene-environment interactions, oxidative stress, systemic inflammation, cell dysfunction, and psychosocial influences. The development of MCS may be attributed to the sensitization of transient receptor potential (TRP) receptors, notably TRPV1 and TRPA1. Capsaicin inhalation challenge studies demonstrated that TRPV1 sensitization is manifested in MCS, and functional brain imaging studies revealed that TRPV1 and TRPA1 agonists promote brain-region specific neuronal variations. Unfortunately, MCS has often been inappropriately viewed as stemming exclusively from psychological disturbances, which has fostered patients being stigmatized and ostracized, and often being denied accommodation for their disability. Evidence-based education is essential to provide appropriate support and advocacy. Greater recognition of receptor-mediated biological mechanisms should be incorporated in laws, and regulation of environmental exposures.

Neurological susceptibility to environmental exposures: pathophysiological mechanisms in neurodegeneration and multiple chemical sensitivity.

The World Health Organization lists air pollution as one of the top five risks for developing chronic non-communicable disease, joining tobacco use, harmful use of alcohol, unhealthy diets and physical inactivity. This review focuses on how host defense mechanisms against adverse airborne exposures relate to the probable interacting and overlapping pathophysiological features of neurodegeneration and multiple chemical sensitivity. Significant long-term airborne exposures can contribute to oxidative stress, systemic inflammation, transient receptor subfamily vanilloid 1 (TRPV1) and subfamily ankyrin 1 (TRPA1) upregulation and sensitization, with impacts on olfactory and trigeminal nerve function, and eventual loss of brain mass. The potential for neurologic dysfunction, including decreased cognition, chronic pain and central sensitization related to airborne contaminants, can be magnified by genetic polymorphisms that result in less effective detoxification. Onset of neurodegenerative disorders is subtle, with early loss of brain mass and loss of sense of smell. Onset of MCS may be gradual following long-term low dose airborne exposures, or acute following a recognizable exposure. Upregulation of chemosensitive TRPV1 and TRPA1 polymodal receptors has been observed in patients with neurodegeneration, and chemically sensitive individuals with asthma, migraine and MCS. In people with chemical sensitivity, these receptors are also sensitized, which is defined as a reduction in the threshold and an increase in the magnitude of a response to noxious stimulation. There is likely damage to the olfactory system in neurodegeneration and trigeminal nerve hypersensitivity in MCS, with different effects on olfactory processing. The associations of low vitamin D levels and protein kinase activity seen in neurodegeneration have not been studied in MCS. Table 2 presents a summary of neurodegeneration and MCS, comparing 16 distinctive genetic, pathophysiological and clinical features associated with air pollution exposures. There is significant overlap, suggesting potential comorbidity. Canadian Health Measures Survey data indicates an overlap between neurodegeneration and MCS (p < 0.05) that suggests comorbidity, but the extent of increased susceptibility to the other condition is not established. Nevertheless, the pathways to the development of these conditions likely involve TRPV1 and TRPA1 receptors, and so it is hypothesized that manifestation of neurodegeneration and/or MCS and possibly why there is divergence may be influenced by polymorphisms of these receptors, among other factors.

Risks to Health and Well-Being From Radio-Frequency Radiation Emitted by Cell Phones and Other Wireless Devices.

Radiation exposure has long been a concern for the public, policy makers, and health researchers. Beginning with radar during World War II, human exposure to radio-frequency radiation (RFR) technologies has grown substantially over time. In 2011, the International Agency for Research on Cancer (IARC) reviewed the published literature and categorized RFR as a "possible" (Group 2B) human carcinogen. A broad range of adverse human health effects associated with RFR have been reported since the IARC review. In addition, three large-scale carcinogenicity studies in rodents exposed to levels of RFR that mimic lifetime human exposures have shown significantly increased rates of Schwannomas and malignant gliomas, as well as chromosomal DNA damage. Of particular concern are the effects of RFR exposure on the developing brain in children. Compared with an adult male, a cell phone held against the head of a child exposes deeper brain structures to greater radiation doses per unit volume, and the young, thin skull's bone marrow absorbs a roughly 10-fold higher local dose. Experimental and observational studies also suggest that men who keep cell phones in their trouser pockets have significantly lower sperm counts and significantly impaired sperm motility and morphology, including mitochondrial DNA damage. Based on the accumulated evidence, we recommend that IARC re-evaluate its 2011 classification of the human carcinogenicity of RFR, and that WHO complete a systematic review of multiple other health effects such as sperm damage. In the interim, current knowledge provides justification for governments, public health authorities, and physicians/allied health professionals to warn the population that having a cell phone next to the body is harmful, and to support measures to reduce all exposures to RFR.

Chelation: harnessing and enhancing heavy metal detoxification--a review.

Toxic metals such as arsenic, cadmium, lead, and mercury are ubiquitous, have no beneficial role in human homeostasis, and contribute to noncommunicable chronic diseases. While novel drug targets for chronic disease are eagerly sought, potentially helpful agents that aid in detoxification of toxic elements, chelators, have largely been restricted to overt acute poisoning. Chelation, that is multiple coordination bonds between organic molecules and metals, is very common in the body and at the heart of enzymes with a metal cofactor such as copper or zinc. Peptides glutathione and metallothionein chelate both essential and toxic elements as they are sequestered, transported, and excreted. Enhancing natural chelation detoxification pathways, as well as use of pharmaceutical chelators against heavy metals are reviewed. Historical adverse outcomes with chelators, lessons learned in the art of using them, and successes using chelation to ameliorate renal, cardiovascular, and neurological conditions highlight the need for renewed attention to simple, safe, inexpensive interventions that offer potential to stem the tide of debilitating, expensive chronic disease.

Interactions of commonly used dietary supplements with cardiovascular drugs: a systematic review.

BACKGROUND: The objective of this systematic review was to examine the benefits, harms and pharmacokinetic interactions arising from the co-administration of commonly used dietary supplements with cardiovascular drugs. Many patients on cardiovascular drugs take dietary supplements for presumed benefits and may be at risk for adverse supplement-drug interactions. METHODS: The Allied and Complementary Medicine Database, the Cochrane Library, EMBASE, International Bibliographic Information on Dietary Supplements and MEDLINE were searched from the inception of the review to October 2011. Grey literature was also reviewed.Two reviewers independently screened records to identify studies comparing a supplement plus cardiovascular drug(s) with the drug(s) alone. Reviewers extracted data using standardized forms, assessed the study risk of bias, graded the strength of evidence and reported applicability. RESULTS: Evidence was obtained from 65 randomized clinical trials, 2 controlled clinical trials and 1 observational study. With only a few small studies available per supplement, evidence was insufficient for all predefined gradable clinical efficacy and harms outcomes, such as mortality and serious adverse events. One long-term pragmatic trial showed no benefit from co-administering vitamin E with aspirin on a composite cardiovascular outcome. Evidence for most intermediate outcomes was insufficient or of low strength, suggesting no effect. Incremental benefits were noted for triglyceridemia with omega-3 fatty acid added to statins; and there was an improvement in levels of high-density lipoprotein cholesterol with garlic supplementation when people also consumed nitrates CONCLUSIONS: Evidence of low-strength indicates benefits of omega-3 fatty acids (plus statin, or calcium channel blockers and antiplatelets) and garlic (plus nitrates or warfarin) on triglycerides and HDL-C, respectively. Safety concerns, however, persist.

Arsenic, cadmium, lead, and mercury in sweat: a systematic review.

Arsenic, cadmium, lead, and mercury exposures are ubiquitous. These toxic elements have no physiological benefits, engendering interest in minimizing body burden. The physiological process of sweating has long been regarded as "cleansing" and of low risk. Reports of toxicant levels in sweat were sought in Medline, Embase, Toxline, Biosis, and AMED as well as reference lists and grey literature, from inception to March 22, 2011. Of 122 records identified, 24 were included in evidence synthesis. Populations, and sweat collection methods and concentrations varied widely. In individuals with higher exposure or body burden, sweat generally exceeded plasma or urine concentrations, and dermal could match or surpass urinary daily excretion. Arsenic dermal excretion was severalfold higher in arsenic-exposed individuals than in unexposed controls. Cadmium was more concentrated in sweat than in blood plasma. Sweat lead was associated with high-molecular-weight molecules, and in an interventional study, levels were higher with endurance compared with intensive exercise. Mercury levels normalized with repeated saunas in a case report. Sweating deserves consideration for toxic element detoxification. Research including appropriately sized trials is needed to establish safe, effective therapeutic protocols.

Environmental determinants of chronic disease and medical approaches: recognition, avoidance, supportive therapy, and detoxification.

The World Health Organization warns that chronic, noncommunicable diseases are rapidly becoming epidemic worldwide. Escalating rates of neurocognitive, metabolic, autoimmune and cardiovascular diseases cannot be ascribed only to genetics, lifestyle, and nutrition; early life and ongoing exposures, and bioaccumulated toxicants may also cause chronic disease. Contributors to ill health are summarized from multiple perspectives--biological effects of classes of toxicants, mechanisms of toxicity, and a synthesis of toxic contributors to major diseases. Healthcare practitioners have wide-ranging roles in addressing environmental factors in policy and public health and clinical practice. Public health initiatives include risk recognition and chemical assessment then exposure reduction, remediation, monitoring, and avoidance. The complex web of disease and environmental contributors is amenable to some straightforward clinical approaches addressing multiple toxicants. Widely applicable strategies include nutrition and supplements to counter toxic effects and to support metabolism; as well as exercise and sweating, and possibly medication to enhance excretion. Addressing environmental health and contributors to chronic disease has broad implications for society, with large potential benefits from improved health and productivity.

Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review.

BACKGROUND: The evidence for testing thiopurine S-methyltransferase (TPMT) enzymatic activity or genotype before starting therapy with thiopurine-based drugs is unclear. PURPOSE: To examine the sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in adults and children with chronic inflammatory diseases. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Library, and Ovid HealthSTAR (from inception to December 2010) and BIOSIS and Genetics Abstracts (to May 2009). STUDY SELECTION: Two reviewers screened records and identified relevant studies in English. DATA EXTRACTION: Data on patient characteristics, outcomes, and risk for bias were extracted by one reviewer and independently identified by another. DATA SYNTHESIS: 54 observational studies and 1 randomized, controlled trial were included. Insufficient evidence addressed the effectiveness of pretesting. Genotyping sensitivity to identify patients with low and intermediate TPMT enzymatic activity ranged from 70.33% to 86.15% (lower-bound 95% CI, 54.52% to 70.88%; upper-bound CI, 78.50% to 96.33%). Sparse data precluded estimation of genotype sensitivity to identify patients with low to absent enzymatic activity. Genotyping specificity approached 100%. Compared with noncarriers, heterozygous and homozygous genotypes were both associated with leukopenia (odds ratios, 4.29 [CI, 2.67 to 6.89] and 20.84 [CI, 3.42 to 126.89], respectively). Compared with intermediate or normal activity, low TPMT enzymatic activity was significantly associated with myelotoxicity and leukopenia. LIMITATION: Available evidence was not rigorous and was underpowered to detect a difference in outcomes. CONCLUSION: Insufficient evidence addresses the effectiveness of TPMT pretesting in patients with chronic inflammatory diseases. Estimates of the sensitivity of genotyping are imprecise. Evidence confirms the known associations of leukopenia or myelotoxicity with reduced TPMT activity or variant genotype. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Pre-analytic and analytic sources of variations in thiopurine methyltransferase activity measurement in patients prescribed thiopurine-based drugs: A systematic review.

OBJECTIVES: Low thiopurine S-methyltransferase (TPMT) enzyme activity is associated with increased thiopurine drug toxicity, particularly myelotoxicity. Pre-analytic and analytic variables for TPMT genotype and phenotype (enzyme activity) testing were reviewed. DESIGN AND METHODS: A systematic literature review was performed, and diagnostic laboratories were surveyed. RESULTS: Thirty-five studies reported relevant data for pre-analytic variables (patient age, gender, race, hematocrit, co-morbidity, co-administered drugs and specimen stability) and thirty-three for analytic variables (accuracy, reproducibility). TPMT is stable in blood when stored for up to 7 days at room temperature, and 3 months at -30°C. Pre-analytic patient variables do not affect TPMT activity. Fifteen drugs studied to date exerted no clinically significant effects in vivo. Enzymatic assay is the preferred technique. Radiochemical and HPLC techniques had intra- and inter-assay coefficients of variation (CVs) below 10%. CONCLUSION: TPMT is a stable enzyme, and its assay is not affected by age, gender, race or co-morbidity.

Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.

OBJECTIVES: To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications. DATA SOURCES: MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records. REVIEW METHODS: A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations. RESULTS: 1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous. CONCLUSIONS: There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.

Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia.

BACKGROUND: Statin therapy effectively prevents vascular disease, but treatment targets are often not achieved. PURPOSE: To compare the benefits and harms of high-dose statin monotherapy with those of combination therapy in adults at high risk for coronary disease. DATA SOURCES: English-language records from MEDLINE (1966 to 2009), EMBASE (1980 to 2009), and the Cochrane Library (third quarter of 2008). STUDY SELECTION: A reviewer screened records, and a second reviewer verified selection of randomized, controlled trials in adult patients that compared combinations of statins and bile-acid sequestrants, fibrates, ezetimibe, niacin, or omega-3 fatty acids with statin monotherapy, as well as nonrandomized comparative studies that were longer than 24 weeks and reported clinical and harms outcomes. DATA EXTRACTION: Data were abstracted for studies by using standardized forms, and study quality was rated with a standardized scale and strength of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: 102 studies met eligibility criteria. The main analysis compared combination therapy with high-dose statin monotherapy in high-risk patients. Very-low-strength evidence showed that statin-ezetimibe (2 trials; n = 439) and statin-fibrate (1 trial; n = 166) combinations did not reduce mortality more than high-dose statin monotherapy. No trials compared the effect of combination therapy versus high-dose statin monotherapy on the incidence of myocardial infarction, stroke, or revascularization procedures. Two statin-ezetimibe trials (n = 295) demonstrated higher low-density lipoprotein cholesterol goal attainment with combination therapy (odds ratio, 7.21 [95% CI, 4.30 to 12.08]). Trials in lower-risk patients did not show a difference in mortality. LIMITATIONS: Studies were generally short, focused on surrogate outcomes, and were heterogeneous in the sample's risk for coronary disease. Few studies examined treatment combinations other than statin-ezetimibe. CONCLUSION: Limited evidence suggests that combinations of lipid-lowering agents do not improve clinical outcomes more than high-dose statin monotherapy. Very-low-quality evidence favors statin-ezetimibe treatment for attainment of low-density lipoprotein cholesterol goals. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Standard concentrations of high-alert drug infusions across paediatric acute care.

BACKGROUND: To reduce the risk of medication errors in paediatric patients, the Canadian Council on Health Services Accreditation endorsed the standardization and limiting of drug concentrations available within an organization. METHODS: Standard concentrations (SCs) were implemented in the emergency department, operating room and paediatric intensive care unit at the Children's Hospital of Eastern Ontario in Ottawa, Ontario. The change in practice involved addressing concerns raised during stakeholder consultations, developing a computer program, and educating and testing staff in the new method. The software for SC selection and infusion rate calculation featured redundant inputs, a 'deviation' column comparing the prescribed and infused doses, and a printout of patient information that also facilitated dose verification back-calculation. RESULTS: The major barrier to acceptance of SCs was possible fluid overload in lower weight patients. Thus, infusions received by 48 successive infants in the paediatric intensive care unit were compared with theoretical SC infusions. Volumes were not significantly increased, and there was no trend toward proportionally larger volumes in lower weight patients. Medication error reporting was very low before implementation, and SC errors remained low; new online reporting led to higher reporting of other errors after implementation. A survey indicated excellent staff acceptance and beliefs that patient safety and continuity of care were improved. INTERPRETATION: SCs were successfully instituted with computer support, in lieu of 'smart pumps,' across multiple critical care units in a paediatric institution. The initial program is being expanded to 40 continuous infusion drugs, plus paediatric advanced life support bolus medications.