Convulsions and hypoglycemia due to tetramethyl succinonitrile intoxication in the polyvinyl chloride (PVC) industry: A 4-year follow-up

Objectives: Exposure and clinical data concerning cases of toxic convulsions and hypoglycemia due to tetramethyl succinonitrile (TMSN) exposure are reported. Material and Methods: Forty-four workers exposed to TMSN in the PVC production plant participated in occupational health medical check-ups including medical history, clinical examination and clinical chemistry. A 4-year follow-up was performed. To evaluate occupational exposure, measurements of TMSN in the ambient air as well as personal air sampling were conducted. Results: Four workers suffered from convulsions with reversible pathologic EEG and 16 other persons were hypoglycemic. Other frequent symptoms included headaches, dizziness and unpleasant taste sensations. TMSN levels had been clearly above the Swiss occupational exposure limit value (MAK). Occupational hygiene interventions resulted in a reduction of the TMSN concentration below the MAK value. TMSN related symptoms have not been observed anymore in the 4-year follow-up. Conclusion: TMSN is a convulsive substance which in humans has also a hypoglycemic effect

Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards

Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence-based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard

Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case fora causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding

A proposal for calculating the no-observed-adverse-effect level (NOAEL) for organic compounds responsible for liver toxicity based on their physicochemical properties

Objectives: Both environmental and occupational exposure limits are based on the no-observed-adverse-effect level (NOAEL), lowest-observed-adverse-effect level (LOAEL) or benchmark dose (BMD) deriving from epidemiological and experimental studies. The aim of this study is to investigate to what extent the NOAEL values for organic compounds responsible for liver toxicity calculated based on their physicochemical properties could be used for calculating occupational exposure limits. Material and Methods: The distribution coefficients from air to the liver (log Kliver) were calculated according to the Abraham solvation equation. NOAEL and LOAEL values for early effects in the liver were obtained from the literature data. The descriptors for Abraham's equation were found for 59 compounds, which were divided into 2 groups: "non-reactive" (alcohols, ketones, esters, ethers, aromatic and aliphatic hydrocarbons, amides) and "possibly reactive" (aldehydes, allyl compounds, amines, benzyl halides, halogenated hydrocarbons, acrylates). Results: The correlation coefficients between log-log K and log NOAEL for non-reactive and reactive compounds amounted to r = -0.8123 and r = -0.8045, respectively, and were statistically significant. It appears that the Abraham equation could be used to predict the NOAEL values for compounds lacking information concerning their liver toxicity. Conclusions: In view of the tendency to limit animal testing procedures, the method proposed in this paper can improve the practice of setting exposure guidelines for the unstudied compounds