Efficacy and Safety of SHR0302, a Highly Selective Janus Kinase 1 Inhibitor, in Patients with Moderate to Severe Atopic Dermatitis: A Phase II Randomized Clinical Trial.

BACKGROUND: Atopic dermatitis is a chronic, inflammatory condition causing a substantial burden to patients and caregivers. SHR0302 is an oral, highly selective, Janus kinase 1 inhibitor under investigation for inflammatory skin diseases. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of SHR0302 in Chinese patients with moderate to severe atopic dermatitis. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase II trial was conducted in China between October 2019 and August 2020. PARTICIPANTS: Patients (n = 105) aged 18-75 years with moderate to severe dermatitis and nonresponsive or intolerant to topical or conventional systemic treatments were included. INTERVENTIONS: Patients were randomly assigned in a ratio of 1:1:1 to receive SHR0302 4 mg once daily, SHR0302 8 mg once daily, or placebo for 12 weeks. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion of patients achieving Investigator's Global Assessment (IGA) response (IGA of 0 [clear] or 1 [almost clear] with improvement of ≥2 grades) at week 12. Secondary efficacy assessments included Eczema Area and Severity Index (EASI) and pruritus Numerical Rating Scale (NRS) scores. RESULTS: At week 12, IGA response was achieved in nine patients (25.7%; 90% confidence interval [CI] 13.6-37.9%; p = 0.022) in the SHR0302 4 mg group, 19 patients (54.3%; 90% CI 40.4-68.1%; p < 0.001) in the SHR0302 8 mg group, and two patients (5.7%; 90% CI 0.0-12.2%) in the placebo group. EASI75 was achieved in 51.4% (p = 0.013), 74.3% (p < 0.001), and 22.9% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively, while an NRS ≥3-point improvement occurred in 65.7% (p < 0.001), 74.3% (p < 0.001), and 22.9% of patients, respectively. Treatment-emergent adverse events were reported in 60.0%, 68.6%, and 51.4% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively. The adverse events were mild in most cases. Three serious adverse events were reported, all being worsening of atopic dermatitis. No serious infection was reported. CONCLUSIONS AND RELEVANCE: Oral SHR0302 was effective and well tolerated in Chinese adult patients with moderate to severe atopic dermatitis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04162899; URL: https://clinicaltrials.gov/ . Date first registered: 14 November 2019.

The acidified drinking water-induced changes in the behavior and gut microbiota of wild-type mice depend on the acidification mode.

Acidification of drinking water to a pH between 2.5 and 3.0 is widely used to prevent the spread of bacterial diseases in animal colonies. Besides hydrochloric acid (HCl), sulfuric acid (H2SO4) is also used to acidify drinking water. Here we examined the effects of H2SO4-acidified drinking water (pH = 2.8) received from weaning (postnatal day 21) on the behavior and gut microflora of 129S6/SvEv mice, a mouse strain commonly used in transgenic studies. In contrast to HCl-acidified water, H2SO4-acidified water only temporarily impaired the pole-descending ability of mice (at 3 months of age), and did not change the performance in an accelerating rotarod test. As compared to 129S6/SvEv mice receiving non-acidified or HCl-acidified drinking water, the gut microbiota of 129S6/SvEv mice on H2SO4-acidified water displayed significant alterations at every taxonomic level especially at 6 months of age. Our results demonstrate that the effects of acidified drinking water on the behavior and gut microbiota of 129S6/SvEv mice depends on the acid used for acidification. To shed some light on how acidified drinking water affects the physiology of 129S6/SvEv mice, we analyzed the serum and fecal metabolomes and found remarkable, acidified water-induced alterations.

The Formation, Persistence, and Resistance to Disinfectant of the Erysipelothrix piscisicarius Biofilm.

Erysipelothrix piscisicarius is an emergent pathogen in fish aquaculture, particularly in the ornamental fish trade. Very little is known on the biology of this pathogen; however, the recurrence of infection and disease outbreaks after removing the fish from a system and disinfecting the tank suggest its environmental persistence. Moreover, biofilm lifestyle in E. piscisicarius has been suspected but not previously shown. The purpose of this study was to investigate the formation of biofilms on an abiotic surface in Erysipelothrix spp. We used hydroxyapatite-coated plastic pegs to demonstrate the attachment, growth, and persistence of E. piscisicarius on abiotic surfaces in both fresh and marine environments and to investigate the susceptibility of this pathogen to different disinfectants that are used in the aquaculture industry. E. piscisicarius formed biofilms that persisted significantly longer than planktonic cells did in both freshwater and saltwater over a period of 120 h (P = 0.004). The biofilms were also more resistant to disinfectants than the planktonic cells were. Hydrogen peroxide was the most effective disinfectant against E. piscisicarius, and it eradicated the biofilms and planktonic cells at the recommended concentrations. In contrast, Virkon and bleach were able to eradicate only the planktonic cells. This information should be taken into consideration when developing biosecurity protocols in aquaculture systems, aquariums, and private collections.

The alkylaminoalkanethiosulfuric acids exhibit in-vitro antileishmanial activity against Leishmania (Viannia) braziliensis: a new perspective for use of these schistosomicidal agents.

The alkylaminoalkanethiosulfuric acids (AAATs) are amphipathic compounds effective against experimental schistosomiasis, of low toxicity, elevated bioavailability after a single oral dose and prompt tissue absorption. OBJECTIVES: To explore the in-vitro antileishmanial potential of AAATs using five compounds of this series against Leishmania (Viannia) braziliensis. METHODS: Their effects on promastigotes and axenic amastigotes, and cytotoxicity to macrophages were tested by the MTT method, and on Leishmania-infected macrophages by Giemsa stain. Effects on the mitochondrial membrane potential of promastigotes and axenic amastigotes and DNA of intracellular amastigotes were tested using JC-1 and TUNEL assays, respectively. KEY FINDINGS: The 2-(isopropylamino)-1-octanethiosulfuric acid (I) and 2-(sec-butylamino)-1-octanethiosulfuric acid (II) exhibit activity against both promastigotes and intracellular amastigotes (IC50 25-35 µm), being more toxic to intracellular parasites than to the host cell. Compound I induced a loss of viability of axenic amastigotes, significantly reduced (30%) the mitochondrial membrane potential of both promastigotes and axenic amastigotes and promoted selective DNA fragmentation of the nucleus and kinetoplast of intracellular amastigotes. CONCLUSIONS: In this previously unpublished study of trypanosomatids, it is shown that AAATs could also exhibit selective antileishmanial activity, a new possibility to be investigated in oral treatment of leishmaniasis.

Silagem de dourada Brachyplatystoma rousseauxii (Casteunal, 1855) a partir de diferentes concentrações de ácido acético e ácido sulfúrico / Silage of dourada Brachyplatystoma rousseauxii (Castelnau, 1855) from different concentrations of acetic acid and sulfuric acid

O objetivo deste trabalho foi analisar a estabilidade física e físico-química de silagens com diferentes concentrações de ácido acético e ácido sulfúrico, proferida com resíduos de Brachyplatystoma rousseauxii (Castelnau, 1855) (dourada). O método consistiu da adição de 0,5% de ácido sulfúrico; 3 e 5% de ácido acético (silos diferentes) em resíduos de Dourada. Durante a estocagem foram mensurados os parâmetros: pH, temperatura, umidade, cinzas e lipídios. Os tratamentos demonstraram poucas variações entre si, mantendo-se próximos ao do produto in natura, exceto para os níveis de umidade que apresentaram padrões decrescentes. Contudo, o silo contendo maior concentração de inoculante foi o que apresentou silagem com melhor estabilidade.

Assessment of Chicken Carcass Microbiome Responses During Processing in the Presence of Commercial Antimicrobials Using a Next Generation Sequencing Approach.

The purpose of this study was to 1) identify microbial compositional changes on chicken carcasses during processing, 2) determine the antimicrobial efficacy of peracetic acid (PAA) and Amplon (blend of sulfuric acid and sodium sulfate) at a poultry processing pilot plant scale, and 3) compare microbial communities between chicken carcass rinsates and recovered bacteria from media. Birds were collected from each processing step and rinsates were applied to estimate aerobic plate count (APC) and Campylobacter as well as Salmonella prevalence. Microbiome sequencing was utilized to identify microbial population changes over processing and antimicrobial treatments. Only the PAA treatment exhibited significant reduction of APC at the post chilling step while both Amplon and PAA yielded detectable Campylobacter reductions at all steps. Based on microbiome sequencing, Firmicutes were the predominant bacterial group at the phyla level with over 50% frequency in all steps while the relative abundance of Proteobacteria decreased as processing progressed. Overall microbiota between rinsate and APC plate microbial populations revealed generally similar patterns at the phyla level but they were different at the genus level. Both antimicrobials appeared to be effective on reducing problematic bacteria and microbiome can be utilized to identify optimal indicator microorganisms for enhancing product quality.

Oil crop biomass residue-based media for enhanced algal lipid production.

The aim of this study was to evaluate the use of hydrolysates from acid hydrolysis of four different oil crop biomass residues (OCBR) as low cost culture media for algae growth. The one-factor-at-a-time method was used to design a series of experiments to optimize the acid hydrolysis conditions through examining the total nitrogen, total phosphorus, chemical oxygen demand, and ammonia nitrogen in the hydrolysates. The optimal conditions were found to be using 3% sulfuric acid and hydrolyzing residues at 90 °C for 20 h. The hydrolysates (OCBR media) produced under the optimal conditions were used to cultivate the two algae strains, namely UM258 and UM268. The results from 5 days of cultivation showed that the OCBR media supported faster algae growth with maximal algal biomass yield of 2.7 and 3 g/L, respectively. Moreover, the total lipids for UM258 and UM268 were 54 and 35%, respectively, after 5 days of cultivation, which suggested that the OCBR media allowed the algae strains to accumulate higher lipids probably due to high C/N ratio. Furthermore, over 3% of omega-3 fatty acid (EPA) was produced for the two algae strains. In conclusion, OCBR media are excellent alternative for algae growth and have a great potential for large-scale production of algae-based ingredients for biodiesel as well as high-value food and pharmaceutical products.

Aggravation of cyclophosphamide-induced acute neurological disorders under conditions of artificial acidification of chyme in rats.

The effect of artificial acidification of the intestinal content on neurological manifestations of acute severe cyclophosphamide intoxication was studied in rats. The animals were gavaged with 20 ml/kg sulfuric (0.05 M), hydrochloric, boric, or lactic acids (0.1 M) 3 h before intraperitoneal injections of the cytostatic in doses of 0, 200, 600, or 1000 mg/kg. The decrease in pH (by.0) and ammonia-producing activity of the cecal chyme developed within 3 h after administration of acids. Cyclophosphamide caused hyperammonemia; glutamine/ammonia and urea/ammonia ratios in the blood decreased. These changes augmented after administration of acids (boric acid produced maximum and lactic acid minimum effects). Acid treatment resulted in greatest elevation of ammonia level in the portal venous blood and a lesser elevation in the vena cava posterior blood. Acid treatment promoted manifestation of cyclophosphamide neurotoxic effect and animal death. Hence, acidification of the chyme inhibited the formation of ammonia in it, while ammonia release from the gastrointestinal tract into the blood increased; the treatment augmented hyperammonemia and aggravated the neurological manifestations of cyclophosphamide intoxication.

Aquaculture fouling: Efficacy of potassium monopersulphonate triple salt based disinfectant (Virkon® Aquatic) against Ciona intestinalis.

With the increasing spread of invasive marine species and their detrimental effects on aquaculture operations globally, mitigation strategies need to be optimized to mitigate economic impacts. The efficacy of a potassium monopersulphonate triple salt based disinfectant used in the aquaculture industry (Virkon® Aquatic at 0.5-5%) was evaluated against the solitary tunicate Ciona intestinalis, as well as the susceptibility of three different age groups of C. intestinalis to the treatment and the effect of the disinfectant on mussel mortality. Younger C. intestinalis were most affected by all treatments, and almost all immersion applications significantly decreased the biomass of C. intestinalis compared to untreated plates. Disinfectant solutions of ≥ 1% reduced biomass below pre-treatment levels. Mussel mortality was low, especially for solutions <3%. C. intestinalis should be treated 4 weeks post-settlement to maximize antifouling treatment effects. Immersion in 3% disinfectant for 30 s reduced the biomass of C. intestinalis by up to 89% and would be feasible in field applications using existing treatment equipment.

Sulfuric acid injury.

Injuries and deaths from exposure to caustic substances are infrequently reported in the forensic pathology literature. Strong acids like sulfuric acid produce a predictable set of injuries with cutaneous exposure and ingestion. Multiple factors influence the resultant pathology, but from the perspective of the autopsy pathologist, the most important is the length of postingestion survival. We report the case of a young man whose desire to 'clean his honor' was manifested through the consumption of a large quantity of sulfuric acid drain cleaner. Although a myriad of physical findings were present at autopsy, the majority of these most likely represented the postmortem action of sulfuric acid on tissues.

Toxicological interactions in the respiratory system after inhalation of ozone and sulfuric acid aerosol mixtures.

A factorial design study was performed to examine the acute effects of inhaled acid particles alone and in mixtures with ozone to test the hypothesis that acid particles and ozone would act synergistically. Sprague-Dawley rats were exposed nose-only for a single 4-h period to all 9 possible combinations of purified air and 2 concentrations each of O(3) (0.3 and 0.6 ppm) and submicrometer (0.3 µm mass median diameter [MMD]) sulfuric acid aerosols H(2)SO(4) (0.5 and 1.0 mg/m(3)). Respiratory-tract injury and impairment of alveolar macrophage functions were evaluated. Two-way analyses of variance were used to test for significance of main effects and statistical interactions, and Tukey multiple comparison tests were used to test the significance of differences between group mean values. Addition of H(2)SO(4) to O(3)-containing atmospheres resulted in significant H(2)SO(4) concentration-dependent reductions in O(3)-induced inflammatory responses, and H(2)SO(4), alone and in combination with O(3), depressed some functions of innate immunity. DNA synthesis in nasal, tracheal, and lung tissue following pollutant exposure, which is an index of injury or killing of epithelial cells, was significantly increased by O(3) but not by H(2)SO(4) when administered alone, compared to purified air. When administered with O(3), H(2)SO(4) did not reduce the effects of O(3) on DNA synthesis in the trachea or the lung, but did reduce the DNA synthesis response to O(3) in the nose. No significant changes in antibody-directed Fc receptor (FcR) binding of sheep red blood cells by alveolar macrophages were observed, but macrophage phagocytic activity was significantly reduced by the pollutant exposures. In summary, the results of this study indicate significant interactions between O(3) and H(2)SO(4) in concurrent exposures; however, the findings do not support the hypothesis that O(3) and H(2)SO(4) act synergistically in rats after single 4-h exposures.

Virucidal activity of Virkon S on human enterovirus.

The efficacy of Virkon S, a commercial disinfectant as a virucidal spray against human enterovirus 71 (HEV71), the causative agent of the fatal form of hand, foot and mouth disease was examined. At least one log10 reduction of HEV71 titer was achieved when one spray of Virkon (1% or 2%) with ten minutes of contact time was applied. The infectivity was completely lost when four sprays of 1% or 2% Virkon were applied, suggesting that at least four sprays of 1% Virkon to the surface bound HEV71 was necessary to completely inactivate the virus. These findings suggest that Virkon S at the proper concentration is suitable to be used as an effective and easy to use disinfectant against HEV71.

Relative acidifying activity of anionic salts commonly used to prevent milk fever.

High cation diets can cause milk fever in dairy cows as they induce a metabolic alkalosis reducing the ability of the cow to maintain calcium homeostasis at the onset of lactation. Adding anions to the diet can offset the effect of the high cation forages by inducing a mild metabolic acidosis, restoring the ability to maintain calcium homeostasis. The difference in mEq of dietary cations and anions (DCAD) is most often expressed as (Na(+) + K+) - (Cl- + S(--)). This equation implies that a mEq of chloride and a mEq of sulfate are equipotent in their ability to alter acid-base balance of the cow. Using blood and urine pH to monitor effects on acid-base balance, experiments were conducted to test the relative acidifying activity of various sulfate and chloride anion sources in nonpregnant, nonlactating Jersey cows. Across all experiments, chloride proved to have about 1.6 times the acidifying activity of sulfate. Calcium and magnesium, ignored by the common DCAD equation, had a small but significant alkalinizing effect when accompanying chloride or sulfate. The ranking of the anion sources tested at a dose of 2 Eq/d, from most to least potent urine acidifier, was hydrochloric acid, ammonium chloride, calcium chloride, calcium sulfate, magnesium sulfate, and sulfur. These data should allow more accurate prediction of the response of late gestation cows to dietary cation-anion manipulation.

Responses in the respiratory tract of rats following exposure to sulphuric acid aerosols for 5 or 28 days.

Sulphuric acid mists have been classified by the International Agency for Research on Cancer as being carcinogenic to humans based on epidemiological findings of respiratory tract tumours. To determine if early changes in the respiratory tract following exposure to sulphuric acid (H(2)SO(4)) aerosols are consistent with the possible development of tumours after extended periods of exposure, groups of female rats were exposed to respirable aerosols of H(2)SO(4) at target concentrations of 0, 0.2, 1.0 or 5.0 mg m(-3) for 6 h per day for either 5 days or for 5 days a week over a 28-day period. Additional groups exposed to 0 or 5.0 mg m(-3) over the 28-day period were retained after exposure for 4 or 8 weeks to assess recovery. Histopathological examinations and quantitative cell proliferation measurements were conducted on the nasal passages, larynx and lung. Achieved concentrations were 0.3, 1.38 and 5.52 mg m(-3) H(2)SO(4). Histological and cell proliferative changes were confined to the larynx and no effects were seen in the nasal passages or lungs. At the two highest concentrations, squamous metaplasia accompanied by significant cell proliferation was apparent after 5 and 28 days of exposure and there was a reduction in the severity of the pathological changes following the recovery periods. No effects were seen at 0.3 mg m(-3) after 5 days of exposure and only minimal metaplastic change was seen after 28 days in a few animals and was not accompanied by cell proliferation. The toxicological relevance of these findings is discussed.

Suspected nasopharyngeal carcinoma in three workers with long-term exposure to sulphuric acid vapour.

Sulphuric acid vapour has been suspected of being an industrial carcinogen. In this study, a cluster is presented of three patients with nasopharyngeal carcinoma (NPC) who worked in the same building of a telecommunications conveyance station in southern Taiwan with long term exposure to sulphuric acid vapour concentrations as high as 0.18 mg/m3. All three workers were diagnosed with NPC within a 5 month period between September 1992, and March 1993. Compared with 19 other healthy workers from the same building, these three workers with NPC had worked significantly longer in this building than had the others (mean (SD) (years): 12.7 (0.6) v 7.4 (4.4); p = 0.01). With an in situ nucleic acid hybridisation and immunostaining method for colocalised Epstein-Barr virus (EBV) and secretory component (SC) protein among biopsy specimens of these three patients with NPCs, it was found that some tumour cells did not contain EBV and SC protein staining signals. These results indicate that EBV infection is not the only risk factor for NPC and long term exposure to relatively low concentrations of sulphuric acid vapour may be associated with the development of NPC.

Ventilatory responses in awake guinea pigs exposed to acid aerosols.

This study reports experiments designed to evaluate the dose and temporal effects of an atmospheric pollutant, sulfuric acid (H2SO4) aerosol, on the dynamic components of the respiratory cycle. Ventilation was measured in a whole-body barometric plethysmograph in unanesthetized, unrestrained animals following a 4-h exposure to H2SO4 aerosol at 14.1, 20.1, or 43.3 mg/m3. Lung injury was assessed by histopathology and bronchoalveolar lavage (BAL). Aerosol exposure with H2SO4 caused marked alterations in both the magnitude and composition of the ventilatory response, which were both dose and time dependent. At the highest concentration tested, there was a significant increase in tidal volume (deltaVt) and a decrease in breathing frequency (f) immediately after exposure. Analysis of BAL fluid at this time showed increased inflammatory cells and protein in the acid exposed animals, and histology showed hyaline membranes and acute inflammatory cells in the proximal acinar region. By 24 h postexposure, f significantly increased whereas deltaVt decreased. This pattern of breathing was interspersed with short periods of apnea. The onset of rapid, shallow breathing was associated with histological evidence of diffuse pulmonary edema. By contrast, the immediate postexposure period at the lowest concentration of H2SO4 aerosol was characterized by a significant increase in f and little or no effect on deltaVt. These effects diminished with time, and at 24 h postexposure ventilatory parameters were indistinguishable from baseline values. An apparent crossover between the effects associated with the high and low exposure concentrations was seen at the intermediate exposure concentration; however, closer inspection of these findings on an animal-by-animal basis revealed two populations of animals with respiratory characteristics of either the high-exposure or low-exposure groups. The data suggest that the guinea pig exhibits complex interactions between dose and time to response that are consistent with the activation of neural reflexes. The indirect plethysmographic method provides a simple means to assess these responses in a model system that avoids the use of anesthetics, surgery, and restraint.

Aluminum and acid effects on calcium and phosphorus metabolism in young growing chickens (Gallus gallus domesticus) and mallard ducks (Anas platyrhynchos).

Acidification is associated with increased mortality, reduced growth, and bone abnormalities in birds. Associated with acid deposition is an increase in aluminum availability due to solubilization from soil and other sources. (Conversely, experimental diets containing aluminum sulfate have much reduced pHs.) The present studies compare the effects of two levels of dietary acid (sulfuric acid) (0.122 and 0.56 mol H+ per kg feed; 0.056 and 0.277 mol sulfate per kg feed) and dietary aluminum (aluminum sulfate at 0.1 and 0.5%; sulfate at 0. 056 and 0.277 mol sulfate per kg feed) on bone growth, mineralization, and phosphorous/calcium homeostasis in growing birds (chickens and mallard ducks). Growth was reduced by the high acid (chicken) and aluminum (ducks and chickens) diets. A reduction in bone mineralization was observed in birds receiving aluminum-containing diets [low aluminum diet: decreased tibia ash, calcium, and phosphorus (chickens); high aluminum diet: decreased tibia dry weight, % of ash and mg; ash, calcium (chickens, ducks as % of ash), and phosphorus (chickens mg/duck, % of ash)]. Moreover, plasma concentrations of inorganic phosphate were reduced in chicks on the high aluminum diet. There were also marked decreases in bone growth and mineralization [tibia weight, ash (mg), calcium (mg), phosphorus (mg)] and plasma concentrations of 1,25-dihydroxy vitamin D3 in chicks on the high acid diet compared to those on a control diet. These changes were probably due to reduced feed intake; changes in bone indices being of a greater or similar magnitude in pairfed control. There was little change in bone indices, growth rate or feed consumption in ducklings receiving either the low or high acid diets. It is concluded that aluminum directly adversely affected bone mineralization whereas acid effects are mediated in part by changes in feed consumption.

A review of the chronic toxicity, carcinogenicity, and possible mechanisms of action of inorganic acid mists in animals.

Occupational exposure to inorganic acid mists containing sulfuric acid has been associated with increased laryngeal cancer. The primary objective of this review was to compile the literature regarding chronic toxicity and carcinogenicity of inorganic acid mists in laboratory animals. Several chronic toxicity studies had exposures of 1 year or longer. Whereas numbers of animals were limited, no evidence of neoplastic or preneoplastic lesions was reported. Two studies evaluated the carcinogenicity of inorganic acid mists in rats; however, one was limited by a short duration of exposure and the other did not achieve a maximum tolerated dose. A large lifetime study in hamsters evaluated the carcinogenicity of 100 mg/M3 sulfuric acid mist, as well as its ability to act as a promoter or co-carcinogen for benzo(a)pyrene. No evidence of carcinogenic potential was shown. Although an increase in papillomas was noted in the benzo(a)pyrene + H2SO4 group, the co-carcinogenic or promoting potential was considered equivocal. Thus, no evidence from experimental animals strongly supports or refutes the induction of cancer by inorganic acid mists. A possible mechanism that could be associated with inorganic acid mist carcinogenicity relates to the genetic consequences of lowering the pH. Reduced pH can induce chromosomal aberrations, enhance depurination, and deamination of cytidine in DNA. This mechanism has not been evaluated in tissues of the respiratory tract.

Chronic exposure of rats to ozone and sulfuric acid aerosol: biochemical and structural responses.

Groups of rats were exposed to either 0.12 or 0.20 ppm of ozone, 20, 100, or 150 ppm of sulfuric acid aerosol (0.4-0.8 microm diameter), or their mixtures in whole body exposure chambers for up to 90 days. Matched control animals were exposed to filtered air in comparable chambers. The rats were examined biochemically and morphometrically for centriacinar fibrosis or other indicators of pollutant-induced changes in the terminal bronchiole-alveolar duct junction region of the lung at the end of the exposures. By evaluating different markers of lung injury, we had previously demonstrated a synergistic interaction between ozone and sulfuric acid aerosol after acute exposures to these same concentrations of the pollutants. The present experiments were designed to answer the question of whether there was any interaction between ozone and respirable sized aerosols of sulfuric acid, synergistic or antagonistic, after chronic exposures. Exposure of rats to 0.12 or 0.20 ppm of ozone elicited tissue and cellular changes at the bronchiole-alveolar duct junction. Concurrent exposure to sulfuric acid aerosol did not affect the extent or magnitude of these changes. Intermittent exposure (12 h per day) to ozone, with or without the acid aerosol, elicited a greater response than did continuous exposure (24 h per day). No consistent effects of exposure to sulfuric acid aerosol alone were observed, either morphometrically or biochemically. The biochemical data were consistent with the morphometric analyses, showing trends towards or significantly increased lung 4-hydroxyproline content in the rats exposed to ozone, with or without sulfuric acid aerosol, in the intermittent exposure experiment, but not after continuous exposure. No interactive effects between ozone and sulfuric acid aerosol were observed with any of the biochemical parameters examined. We conclude that ozone and sulfuric acid aerosols do not exhibit synergistic interactions after chronic exposures (90 days) of rats to the concentrations tested in this study, which correspond to concentrations showing synergistic interactions in previously performed acute studies. We also observed that exposure of rats to ozone for 12 h per day elicited greater lung changes, which we interpret to indicate a mild fibrotic response, than did exposure of rats for 24 h per day, whether or not there was accompanying exposure to the acid aerosol.