Arlean Rohde

Toxicity and metabolism of methylnaphthalenes: Comparison with naphthalene and 1-nitronaphthalene

Naphthalene and close structural analogues have been shown to cause necrosis of bronchiolar epithelial cells in mice by both inhalation exposure and by systemic administration. Cancer bioassays of naphthalene in mice have demonstrated a slight increase in bronchiolar/alveolar adenomas in female mice, and in inflammation and metaplasia of the olfactory epithelium in the nasal cavity. Similar work in rats demonstrated a significant, and concentration-dependent increase in the incidence of respiratory epithelial adenomas and neuroblastomas in the nasal epithelium of both male and female rats. Although the studies on the acute toxicity of the methylnaphthalene derivatives are more limited, it appears that the species selective toxicity associated with naphthalene administration also is observed with methylnaphthalenes. Chronic administration of the methylnaphthalenes, however, failed to demonstrate the same oncogenic potential as that observed with naphthalene. The information available on the isopropylnaphthalene derivatives suggests that they are not cytotoxic. Like the methylnaphthalenes, 1-nitronaphthalene causes lesions in both Clara and ciliated cells. However, the species selective lung toxicity observed in the mouse with both naphthalene and the methylnaphthalenes is not seen with 1-nitronaphthalene. With 1-nitronaphthalene, the rat is far more susceptible to parenteral administration of the compound than mice. The wide-spread distribution of these compounds in the environment and the high potential for low level exposure to humans supports a need for further work on the mechanisms of toxicity in animal models with attention to whether these processes are applicable to humans. Although it is tempting to suppose that the toxicity and mechanisms of toxicity of the alkylnaphthalenes and nitronaphthalenes are similar to naphthalene, there is sufficient published literature to suggest that this may not be the case. Certainly the enzymes involved in the metabolic activation of each of these substrates are likely to differ. The available data showing extensive oxidation of the aromatic nucleus of naphthalene, nitronaphthalene and the methylnaphthalenes (with some oxidation of the methyl group) contrast with the isopropylnaphthalene derivatives, where the major metabolites involve side chain oxidation. Overall, these data support the view that ring epoxidation is a key step in the process involved in cytotoxicity. Whether the epoxide itself or a downstream metabolite mediates the toxic effects is still not clear even with naphthalene, the best studied of this group of compounds. Additional work is needed in several areas to further assess the potential human health consequences of exposure to these agents. These studies should involve the definition of the extent and severity of methylnaphthalene toxicity after single dose exposures with attention to both the nasal and respiratory epithelia. The cytochromes P450 responsible for the initial activation of these agents in rodents with subsequent complimentary studies in primate models should help determine whether key metabolic processes responsible for toxicity occur also in primates. Finally, the precise involvement of reactive metabolite formation and adduction of cellular proteins in toxicity will be important in not only assessing the potential for human toxicity, but also in developing an understanding of the genetic and environmental factors which could alter the toxicity of these agents.

Review of the Toxicology of Mineral Spirits

This review of the toxicology of mineral spirits covers studies of the major classes of mineral spirits and several toxicologically important mineral spirit constituents. This review cites data from numerous previously unpublished animal toxicology studies conducted on mineral spirits during the past 30 years, expanding the existing database on the toxicology of this group of hydrocarbon solvents. The data can be used to better evaluate the potential effects associated with exposure to these materials, including health and environmental reviews such as the U.S. Environmental Protection Agency High Production Volume (HPV) chemical program and the Organization for Economic Cooperation and Development (OECD) HPV Screening Information Data Set (SIDS) program. The majority of animal toxicology studies in the available literature were conducted on mineral spirits categorized as ASTM D235 Type I Class A (149°C to 213°C boiling range; 8% to 22% aromatics) and demonstrate that Type I Class A mineral spirits have a low order of acute toxicity and do not produce significant systemic effects. Some additional studies conducted with ASTM D235 Type II Class C mineral spirits (177°C to 213°C boiling range; <2% aromatics) suggest that Type II Class C mineral spirits have similar toxicity to Type I Class A mineral spirits, though there is some evidence that Type II, Class C mineral spirits have a lesser degree of central nervous system (CNS) effects than the higher aromatic containing Type I Class A materials. In addition, toxicity data on selected chemical constituents of mineral spirits (e.g., n-nonane, n-decane, n-undecane) indicate that these chemicals have similar toxicological properties to mineral spirits. Overall, the data showed that mineral spirits have a low order of acute toxicity and do not appear to produce toxicologically relevant systemic effects. Ongoing studies are evaluating the concerns associated with chronic low-level exposure and central nervous system effects.

Assessment of petroleum streams for thyroid toxicity

The thyroid gland, and its associated endocrine hormones, is a growing area of interest in regulatory toxicology due to its important role in metabolism, growth and development. This report presents a review of the toxicology data on chemically complex petroleum streams for thyroid hormone effects. Toxicological summaries and studies from all available published and un-published sources were considered, drawing upon the European REACH regulatory submissions for 19 petroleum streams, with in depth review of 11 individual study reports and 31 published papers on related products or environmental settings. Findings relevant to thyroid pathology or thyroid hormone homeostasis were specifically sought, summarized, and discussed. A total of 349 studies of 28-days or longer duration were considered in the review, including data on mice, rats, rabbits, dogs, humans, and fish. The thyroid was almost invariably not a target organ in these studies. Three rodent studies did find thyroid effects; one on a jet fuel product (JP-8), and two studies on a heavy fuel oil product (F-179). The JP-8 product differs from other fuels due to the presence of additives, and the finding of reduced T4 levels in mice in the study occurred at a dose that is above that expected to occur in environmental settings (e.g. 2000mg/kg). The finding for F-179 involved thyroid inflammation at 10-55mg/kg that co-occurred with liver pathology in rats, indicating a possible secondary effect with questionable relevance to humans. In the few cases where findings did occur, the polycyclic aromatic hydrocarbon (PAH) content was higher than in related substances, and, in support of one possible adverse outcome pathway, one in-vitro study reported reduced thyroid peroxidase (TPO) activity with exposure to some PAH compounds (pyrene, benzo(k)fluoranthene, and benzo(e)pyrene). However, it could not be determined from the data available for this review, whether these specific PAH compounds were substantially higher in the JP-8 or F-179 products than in studies in which thyroid effects were not observed. Thus, a few products may carry a weak potential to affect the thyroid at high doses in rodents, possibly through secondary effects on the rodent liver or possibly through a pathway involving the inhibition of TPO by specific members of the PAH family. Human epidemiology evidence found weak and inconsistent effects on the thyroid but without identification of specific chemicals involved. Two studies in petroleum workers, which found a lower rate of morbidity and mortality overall, reported a statistically significant increase in thyroid cancer, but the small number of cases could not exclude confounding variables as possible explanations for the statistical findings. Overall, the available data indicates a low potential for thyroid hormone effects from exposure to petroleum streams, especially when the aromatic content is low. Because regulatory studies for most chemicals do not include detailed thyroid function or receptor studies, it remains possible that subclinical effects on this system may exist that were not detectable using conventional pathology or hormone measurements.

Development of a Multimedia Model for the Fate Prediction of Hydrocarbon Fluids in Agrochemical Formulations

Hydrocarbon (HC) fluids are effective inerts in pesticide formulations. These fluids consist of volatile organic compounds (VOCs) that are assumed to be completely volatilized and undergo subsequent atmospheric reaction that may contribute to ozone formation during field use. However, these assumptions are based on laboratory evaporation tests, which fail to account for other environmentally relevant and competitive fate processes, such as biodegradation, soil sorption, runoff, and leaching. If appropriate input parameters are known, or can be reliably estimated, mass balance multimedia models can be used to characterize the importance and uncertainty of various fate processes and provide a more realistic assessment of the potential contribution to ozone formation. A model has been developed and applied to an agricultural field application scenario. Preliminary results suggest biodegradation and soil sorption are significant fate processes that can reduce the mass of HC VOCs entering the atmosphere by volatilization. The implications of applying multimedia models in assessing potential ozone formation from HC fluids in agricultural uses are further highlighted and preliminary laboratory work to confirm model findings is also discussed.

Assessing the Fate of an Aromatic Hydrocarbon Fluid in Agricultural Spray Applications Using the Three-Stage ADVOCATE Model Framework

Components of emulsifiable concentrates (ECs) used in pesticide formulations may be emitted to air following application in agricultural use and contribute to ozone formation. A key consideration is the fraction of the ECs that is volatilized. This study is designed to provide a mechanistic model framework for estimating emissions of an aromatic hydrocarbon fluid used in ECs based on the results of spray chamber experiments that simulate fate as the fluids become subject to volatilization, sorption to soil, and biodegradation. The results indicate the need to treat the volatilization losses in three stages: (i) losses during spraying, (ii) losses up to 12 h after spraying in which the soil is coated with the ECs, and (iii) subsequent longer term losses in which the ECs become increasingly sorbed and subject to biodegradation. A mass balance model, the agrochemical derived volatile organic compound air transfer evaluation (ADVOCATE) tool, is developed, treating the ECs as seven hydrocarbon component groups, to estimate the volatilization and biodegradation losses using parameters fitted to empirical data. This enables losses to be estimated for each hydrocarbon component under field conditions, thereby providing a basis for improved estimation of ozone formation potential and for designing ECs that have lower emissions.

Simulating and Characterizing Agricultural Ground Applications for Soil VOC Deposition Studies

Reactive volatile organic compounds VOCs play a major role in the formation of photo- chemical oxidants in the atmosphere by reacting with oxides of nitrogen and solar ultraviolet energy pro- ducing ozone, which is a criteria pollutant regulated under the National Ambient Air Quality Standards. The United States is one of the most agriculturally productive countries in the world due in part to the use of chemical pesticides that consist of active ingredients that are typically non-volatile or semi-VOCs and inert ingredients such as solvents, emulsifiers, and diluents that may also be volatile. Presently, the VOC deter- mination of emission factors from agricultural pesticide applications assumes that all of the inert VOC ingredients volatilize. This research focuses on the development of a laboratory methodology for applying agricultural spray formulations in accurate and measurable levels to support VOC deposition onto and loss from soil surfaces. Adapting a laboratory spray table system with a modified spray and deposition sampling scheme resulted in repeatable spray applications, with the deposition pattern being mapped across the treatment area. These mapped deposition values allow for measurements from soil samples to be corre- lated with actual spray deposition. This methodology provides for a rapid and repeatable means for sur- veying VOC deposition and losses from a variety of spray formulations under varying spray rates and spray droplet sizes.

Investigating the Use of Hydrocarbon Fluids in Seed Treatment Formulations

Currently, available seed treatments are most often applied as aqueous dispersions or water-based flowable formulations of the active ingredients. Historically, alternatives to aqueous-based treatment methods have been disfavored because alternative solvents, mainly organic solvents, were believed to be toxic toward seeds (phytotoxic). Prior work has shown that seeds such as corn, cotton, wheat, and soybean may be treated with certain nonaqueous solvents, such as hydrocarbon fluids (e.g., normal paraffinic, isoparaffinic, dearomatized mixed aliphatics, and aromatics), with little or no negative effects observed to the seed. In the study reported here, further investigation into the use of fluids for seed treatments has been carried out, and more intensive testing of the phytotoxicity of fluids to seeds, utilizing harsher conditions over longer periods of time (cold germination, saturated cold germination, accelerated aging tests), has been completed. Results have confirmed the importance of fluid volatility (higher volatility fluids result in less phytotoxic response by seeds) and of treatment rates (lower treatment rates minimize negative effects). Seed sensitivity is also important. Cotton and soybean seeds are essentially unaffected by fluids, while wheat and corn seeds show relatively large effects, mitigated to some extent by high volatility and low treatment rates. Although the underlying reasons are not known, fluid treatment of seeds resulted in improvements in germination rates in the saturated cold test, to a small extent for cotton, and to a much greater extent for wheat. Overall, these results indicate that fluids can play a role in seed treatments. The use of fluids requires a balance of factors around fluid structure, volatility, treatment rate, and seed sensitivity. The goal of this work is to take the learnings from these studies, apply them to a full seed treatment formulation, and identify advantages of a fluid-based seed treatment formulation over an aqueous-based formulation.