Risk factors for the introduction of Salmonella spp. serogroups B and D into Dutch dairy herds.

Salmonella spp. infections in animals are a concern due to their zoonotic nature, welfare effects and economic impact on the livestock industry. To enable targeted surveillance, it is important to identify risk factors for the introduction of Salmonella spp. in a herd. Since 2009, Dutch dairy processors require herds delivering milk to their plants to participate in a Salmonella programme. In this programme, bulk milk is tested three times a year (i.e. test rounds) by ELISA on presence of antibodies against Salmonella spp. serogroups B and D. Based on these bulk milk results we identified newly infected herds, and aimed to identify associated risk factors. Effects of putative risk factors for becoming newly infected were studied using a multivariable population average logistic regression (PA-GEE) model with binomial distribution. Per test round in 2019-2021, 0.85-4.10 % of the Dutch dairy herds at risk became newly infected, with large regional differences. Several risk factors for becoming newly infected in the context of the low herd-level prevalence were identified. The most evident risk factors that were identified were having at least one infected or recently recovered dairy herd within 500 m (OR = 2.67), on-farm presence of pigs (OR = 1.63), introduction of more than 2 cattle from other herds in the previous 12 months (OR = 1.17), being in an area with a relative soil moisture of >0.54 % (OR = 1.31), being located in an area with a high water surface area (>2 %; OR = 1.14) and a larger herd size (OR = 1.65). These results indicate that, in addition to introduction of cattle, local transmission plays an important role in the between-herd transmission of Salmonella spp. Information on risk factors for becoming newly infected based on regularly collected data, can be used to improve surveillance and to implement targeted control measures against salmonellosis.

Stochastic models to simulate paratuberculosis in dairy herds.

Stochastic simulation models are widely accepted as a means of assessing the impact of changes in daily management and the control of different diseases, such as paratuberculosis, in dairy herds. This paper summarises and discusses the assumptions of four stochastic simulation models and their use in the design of certification, surveillance, and control strategies for paratuberculosis in cattle herds. A detailed comparison is made between the Dutch JohneSSim and the Danish PTB-Simherd, using the same context of a set of control strategies in a typical Dutch/Danish herd. The conclusion is that while the models are somewhat different in their underlying principles and do put slightly different values on the different strategies, their overall findings are similar. Therefore, simulation models may be useful in planning paratuberculosis strategies in dairy herds, although as with all models caution is warranted when interpreting and generalising the results.

Actual Versus Optimal Radiotherapy Utilisation for Metastatic Cancer Patients in the 45 and Up Study Cohort, New South Wales.

AIMS: Radiotherapy can provide quality of life and/or survival benefits to patients with metastatic cancer on diagnosis (MCOD). However, little is known about radiotherapy utilisation in this population. We compared the optimal radiotherapy rates with actual uptake for people who present with MCOD in the 45 and Up Study cohort, and examined factors associated with utilisation. MATERIALS AND METHODS: In total, 267 153 individuals aged ≥45 enrolled in the Sax Institute's 45 and Up Study completed a baseline questionnaire during 2006-2009, providing sociodemographic and health information and consent for linkage to administrative health databases. Participants diagnosed up to December 2013 with MCOD were identified in the New South Wales Cancer Registry. Radiotherapy receipt was determined from claims to the Medicare Benefits Schedule and/or records in the New South Wales Admitted Patient Data Collection (2006 to June 2016). The Collaboration for Cancer Outcomes, Research and Evaluation optimal utilisation model was adapted for patients with MCOD to provide a benchmark. RESULTS: Of 17 687 participants diagnosed with cancer after completion of the baseline questionnaire, 2392 had MCOD. Of patients with MCOD, 25% had primary lung cancer, which was the most common site. The actual radiotherapy utilisation rate for all patients was 32.3%, lower than the optimal of 45.0%. From multivariable analysis, patients who were aged ≥80 years and/or needed help with daily tasks and/or had a Charlson Comorbidity Index ≥2 were less likely to receive radiotherapy. CONCLUSIONS: Actual uptake of radiotherapy was below optimal. Elderly patients and/or those with more comorbidities were less likely to receive radiotherapy. These results suggest a potential role for advocacy and education around radiotherapy for these patient groups.

Corrigendum: Control and Eradication Programs for Six Cattle Diseases in the Netherlands.

[This corrects the article DOI: 10.3389/fvets.2021.670419.].

Control and Eradication Programs for Six Cattle Diseases in the Netherlands.

Within the European Union, infectious cattle diseases are categorized in the Animal Health Law. No strict EU regulations exist for control, evidence of disease freedom, and surveillance of diseases listed other than categories A and B. Consequently, EU member states follow their own varying strategies for disease control. The aim of this study was to provide an overview of the control and eradication programs (CPs) for six cattle diseases in the Netherlands between 2009 and 2019 and to highlight characteristics specific to the Dutch situation. All of these diseases were listed as C,D or E in the New Animal Health Law. In the Netherlands, CPs are in place for six endemic cattle diseases: bovine viral diarrhea, infectious bovine rhinotracheitis, salmonellosis, paratuberculosis, leptospirosis, and neosporosis. These CPs have been tailored to the specific situation in the Netherlands: a country with a high cattle density, a high rate of animal movements, a strong dependence on export of dairy products, and a high-quality data-infrastructure. The latter specifically applies to the dairy sector, which is the leading cattle sector in the Netherlands. When a herd enters a CP, generally the within-herd prevalence of infection is estimated in an initial assessment. The outcome creates awareness of the infection status of a herd and also provides an indication of the costs and time to achieve the preferred herd status. Subsequently, the herd enrolls in the control phase of the CP to, if present, eliminate the infection from a herd and a surveillance phase to substantiate the free or low prevalence status over time. The high-quality data infrastructure that results in complete and centrally registered census data on cattle movements provides the opportunity to design CPs while minimizing administrative efforts for the farmer. In the CPs, mostly routinely collected samples are used for surveillance. Where possible, requests for proof of the herd status are sent automatically. Automated detection of risk factors for introduction of new animals originating from a herd without the preferred herd status i.e., free or unsuspected, is in place using centrally registered data. The presented overview may inspire countries that want to develop cost-effective CPs for endemic diseases that are not (yet) regulated at EU level.

Invited review: modeling within-herd transmission of Mycobacterium avium subspecies paratuberculosis in dairy cattle: a review.

Epidemiological models have been developed to test hypotheses on Mycobacterium avium ssp. paratuberculosis (Map) transmission in a herd, and to compare different paratuberculosis control strategies and alternatives for certification-and-surveillance schemes. The models are simplified representations of existing biological processes tailored to the questions they are intended to answer. Such models depend on available knowledge about the underlying processes, notably in relation to pathogen transmission. All decisions relating to integration of specific aspects of the herd structure and transmission mechanisms as well as modeling objective will influence model behavior and simulation results. This paper examines assumptions on pathogen transmission and risk mitigation represented in 8 epidemiological models of within-herd Map transmission in dairy cattle. We describe available models' structure and examine them in the context of current knowledge about host infection and pathogen transmission pathways. We investigate how population structure and herd management are modeled with regard to their influence on contact structure and pathogen transmission. We show that assumptions about routes of transmission and their contribution within a herd vary greatly among models. Gaps of knowledge that are pivotal to defining transmission equations and parameters, such as variation of susceptibility with age and variability of pattern of shedding, are identified. Quantitative estimates of this incomplete information should be targeted by future research. Existing models could be improved by considering indirect transmission via the environment taking account of Map survival and contact structure between animals in a herd, and by including calf-to-calf transmission, which has recently been proven as being important.

Prevalence of VTEC O157 in dairy and veal herds and risk factors for veal herds.

The aim of this study was to determine the herd prevalence of veal and dairy herds and to identify risk factors for VTEC O157 positive veal herds. The study was based on monitoring data from November 1996 through July 2005 of 1051 dairy herds and 930 veal herds. The herd level prevalence (95% CI) was 8.0% (6.4-9.6) for dairy herds and 12.6% (10.5-14.7) for veal herds. Within the population of veal herds, a prevalence of 39.8% (33.9-45.6) was found for pink veal herds (n = 269) and 1.5% (0.7-2.8) for white veal herds (n = 661). Multivariable logistic regression showed that the type of veal (pink vs. white; OR = 21.6; 95% CI: 10.4-45.0), ventilation (mechanical vs. natural; OR = 0.4; 95% CI: 0.2-0.8), time between arrival in the herd and sampling (3-5 months vs. 0-2 months: OR = 2.33; 95% CI: 1.1-5.1, > or = 6 months vs. 0-2 months: OR = 4.11; CI: 1.9-8.9), other feed than the 7 most common (yes vs. no; OR = 2.1; 95% CI: 1.2-3.7) and at least one dog present in the stable (yes vs. no; OR = 2.6; 95% CI: 1.5-4.6) were significantly (P < 0.05) associated with the presence of VTEC O157. The large difference in the VTEC O157 prevalences for pink veal and white veal production might have been caused by a very different management of these type of herds. However, this could not be studied with the data collected.

Knowledge gaps that hamper prevention and control of Mycobacterium avium subspecies paratuberculosis infection.

In the last decades, many regional and country-wide control programmes for Johne's disease (JD) were developed due to associated economic losses, or because of a possible association with Crohn's disease. These control programmes were often not successful, partly because management protocols were not followed, including the introduction of infected replacement cattle, because tests to identify infected animals were unreliable, and uptake by farmers was not high enough because of a perceived low return on investment. In the absence of a cure or effective commercial vaccines, control of JD is currently primarily based on herd management strategies to avoid infection of cattle and restrict within-farm and farm-to-farm transmission. Although JD control programmes have been implemented in most developed countries, lessons learned from JD prevention and control programmes are underreported. Also, JD control programmes are typically evaluated in a limited number of herds and the duration of the study is less than 5 year, making it difficult to adequately assess the efficacy of control programmes. In this manuscript, we identify the most important gaps in knowledge hampering JD prevention and control programmes, including vaccination and diagnostics. Secondly, we discuss directions that research should take to address those knowledge gaps.

Cattle transfers between herds under paratuberculosis surveillance in The Netherlands are not random.

The rate and structure of cattle transfers between 206 Dutch cattle herds with a 'Mycobacterium avium subsp. paratuberculosis (Map)-free' status by November 2002, were analyzed over a 3-year period (November 1999-November 2002). Of the 206 'Map-free' herds, 184 were closed herds during the period studied. In total, 280 cattle had been introduced into 22 herds at an average rate of 0.33 animals per year per 100 cattle present in the 206 herds. Assuming a random herd-contact structure, the observed rate of cattle transfers between certified 'Map-free' herds was sufficiently low to relax the surveillance scheme to biennial herd examinations by pooled fecal culture of all cattle > or =2 years of age. The cattle transfers were not randomly distributed over the herds. Forty-four of the 280 cattle originated from 12 other 'Map-free' herds. The other 236 cattle did not originate from a 'Map-free' herd and were introduced into a herd before it obtained the 'Map-free' status. No cattle were introduced into any of the 'Map-free' herds from which cattle were transferred to other 'Map-free' herds. Thus, continued propagation of the infection by cattle transfers was impossible in the group of herds studied during the study period. Therefore the surveillance scheme may be further relaxed, and may be differentiated regarding the risk herds pose to other herds.

Cardiopulmonary effects in awake rats four and six months after exposure to methyl isocyanate.

Cardiopulmonary function was assessed four and six months after Fischer 344 rats were exposed to 2 hr to 0, 3, or 10 ppm methyl isocyanate (MIC). During assessment, the rats were challenged with 4 and 8% carbon dioxide (CO2) to stimulate ventilatory drive. Minute ventilation (VE) during CO2 challenge was increased in MIC-treated rats compared to controls when examined 4 months after exposure to 10 ppm MIC, suggesting a ventilation/perfusion inequality. An increase in maximum expiratory flow and a decrease in expiratory time indicated increased lung recoil in these rats. Evidence of pulmonary hypertension was observed in electrocardiograms (ECGs) and supported by postmortem analysis that showed a positive association between increased ECG abnormalities and increased right ventricular weights in the rats treated with 10 ppm MIC. At 6 months, forced expiratory flow-volume curves indicated persistent airway obstruction; however, no changes in inspiratory or expiratory resistance were evident. Decreased dynamic compliance and changes in two new measures of lung function (volume and time at zero expiratory intrapleural pressure) suggest that MIC-induced lung dysfunction also exhibited elements of a restrictive disease.

A comparison of delta 9-THC and anandamide induced c-fos expression in the rat forebrain.

Rats were injected with the cannabinoid receptor agonists delta 9-THC (5 mg/kg) or anandamide (20 mg/kg) and assessed for changes in body temperature and locomotor activity. Their brains were then examined for the expression of the immediate early gene c-fos. Similar reductions in body temperature and locomotor activity were seen with delta 9-THC and anandamide although there was evidence, in line with previous reports, to suggest a shorter duration of action of anandamide. delta 9-THC and anandamide caused equally high levels of c-fos expression in the paraventricular nucleus of the hypothalamus and the lateral septum. Both drugs also increased c-fos expression in the central nucleus of the amygdala although the effect was greater with delta 9-THC. Only delta 9-THC caused significant increases in c-fos expression in the nucleus accumbens and caudate-putamen. These differences may be linked to differential activation of cannabinoid receptor subtypes or to differences in efficacy in activating second messenger systems linked to cannabinoid receptors. These findings complement evidence of qualitative differences in the actions of anandamide and delta 9-THC emerging from tests of drug discrimination, cross-tolerance, conditioned place preference and anxiety.

Control of VTEC in Dutch livestock and meat production.

The Dutch government and the meat industry, recognising VTEC as having important public health, meat quality and economic implications, have taken a number of initiatives within the last 5 years to control VTEC in livestock and meat. These initiatives, brought together last year in a 'Masterplan VTEC', include short-, middle- and long-term priorities. Short-term priorities include advice on interventions in the cases of an outbreak of VTEC associated with a cattle herd, the implementation of handbooks for Good Manufacturing Practice (GMP) in slaughterhouses and deboning plants, and the execution of an action programme on zero-tolerance to faecal contamination of carcasses. Mid-term activities include surveillance of the occurrence of VTEC and other enteropathogens in livestock and meat, and the investigations of VTEC population dynamics in dairy farms, transportation and farm hygiene. In the longer term, this programme aims to produce a system of Integrated Quality Assurance, consolidating effective measures to control VTEC in Dutch livestock and meat, and integrating emerging means for control and prevention.

[Integrated disease control in dairy herds. A case study from the veterinarians' viewpoint]. / Integrale dierziektebestrijding op melkveebedrijven. Visie van rundveedierenartsen op een casus.

Integrated control of bovine virus diarrhoea virus, bovine herpesvirus-1, Leptospira interrogans serovar hardjo subtype hardjobovis, Mycobacterium avium subsp. paratuberculosis, and Salmonella dublin in dairy herds may provide economic benefits superior to those obtained by sequential disease control, because, among other things, it allows optimization of voluntary culling. However, in practice there are no adequate instruments to establish priorities in voluntary culling. Therefore, in this study the priorities in decision-making for voluntary culling of infected cattle, as indicated by more than 300 cattle veterinarians, were analysed. Based on our results and supplementary considerations, the priorities for voluntary culling in the Netherlands can be ranked as: 1st. cull S. dublin carriers, 2nd. cull persistently infected BVDV carriers, 3rd. cull paratuberculosis faecal culture positive cattle and their last offspring, 4th. cull, in paratuberculosis infected herds, paratuberculosis ELISA positive cattle and their last offspring and cull, in low prevalence herds, BHV1 gE-positive cattle, and 5th. cull leptospirosis seropositive cattle. Since this ranking was based on one case study only, other priorities may prevail in other herds.

[Prevalence of chronic wasting in Dutch dairy herds with a history of chronic health problems]. / Prevalentie van slijtend rundvee op Nederlandse melkveebedrijven met een historie van chronische gezondheidsproblemen.

The prevalence of chronic wasting in cattle in March and April 2000 was studied on 218 dairy farms with a history of health problems accompanied by wasting, following reports in the media suggesting that chronic wasting was a substantial problem on Dutch dairy farms. A telephone call revealed that the health problems had resolved on 41 farms; 16 of these farms had culled all cattle. Two farmers refused co-operation. On the remaining 175 farms the animals were inspected and was completed a questionnaire. A high percentage of culling for of health reasons (on average 18.1% of young stock and adult cattle) and an increased mortality rate (4.8%) were reported on the farms visited. In only two of the 175 inspected herds, more than 20 percent of cattle were found showing signs of wasting. These two herds were identified as 'chronic wasting herds'. The prevalence of such herds was low in this study. Consequently, it is likely that there were very few 'chronic wasting herds' among the whole Dutch dairy population in March/April 2000.

[Vitamin B12 supplementation and milk production on farms with 'chronic wasting' cattle]. / Vitamine B12-suppletie en melkproductie op bedrijven met 'slijtende' runderen.

From early 1999 onwards, cattle health problems accompanied by chronic wasting of unknown aetiology were reported on a number of dairy farms. An association between these health problems and the compulsory use of gE-negative marker vaccines against bovine herpesvirus 1 was presumed by farmers. On one dairy farm an increased milk production of 50% was reported within a few days after parenteral vitamin B12 treatment. Therefore, the current study was designed to determine the effect of parenteral vitamin B12 treatment on the milk production of dairy herds with wasting cattle. A randomized blind trial was performed in five problem herds and two control herds. On each farm five lactating cows were injected intramuscularly with 20 mg vitamin B12 and paired with five untreated lactating cows. The milk production of treated and untreated animals was measured for 19 days following treatment and compared to pre-treatment production. No effect of vitamin B12 treatment on milk production was established on either problem farms or control farms. Neither was a difference detected in the response to vitamin B12 treatment between problem herds and control herds. In a second experiment, parenteral vitamin B12 treatment was applied in three problem herds by local veterinary practitioners. The results of this experiment were in line with the results of the first experiment.

[Outbreak of bovine virus diarrhea on Dutch dairy farms induced by a bovine herpesvirus 1 marker vaccine contaminated with bovine virus diarrhea virus type 2]. / Uitbraak van bovine virus diarree op Nederlandse rundveebedrijven na vaccinatie met een met BVDV type 2 gecontamineerd BHV1 markervaccin.

On 23 February 1999, the Dutch Animal Health Service advised all Dutch veterinary practices to postpone vaccination against bovine herpesvirus 1 (BHV1) immediately. The day before severe disease problems were diagnosed on four dairy farms after vaccination with the same batch of BHV1 marker vaccine. Using monoclonal antibodies, bovine virus diarrhoea virus (BVDV) type 2 was found in the vaccine batch. This paper describes an outbreak of BVDV type 2 infection caused by the use of a batch of modified live BHV1 marker vaccine contaminated with BDVD. Sources of information used were reports of farm visits, minutes of meetings, laboratory results, and oral communications from the people involved. The first symptoms of disease were observed on average six days after vaccination. Morbidity was high on 11 of the 12 farms. On five farms more than 70% of the animals became ill, while on one farm no symptoms could be detected. During the first week after vaccination, feed intake and milk production decreased. During the second week, some animals became clinically diseased having nasal discharge, fever, and diarrhoea. At the end of the second week and at the start of the third week, the number of diseased animals increased rapidly, the symptoms became more severe, and some animals died. Mortality varied among herds. Necropsy most often revealed erosions and ulcers of the mucosa of the digestive tract. In addition, degeneration of the liver, hyperaemia of the abomasum, and swollen mesenterial lymph nodes and swollen spleen were found. On 11 of the 12 farms all animals were culled between 32 and 68 days after vaccination after an agreement was reached with the manufacturer of the vaccine. This was the third outbreak of BVD in cattle after administration of a contaminated vaccine in the Netherlands. The possibilities to prevent contamination of a vaccine as a consequence of infection of fetal calf serum with BVDV are discussed. Improvement of controls to prevent contamination before and during vaccine production, and improvement of the monitoring of side-effects is necessary.

Effects of infectious young stock on results of certification, surveillance and control programmes for paratuberculosis in dairy herds.

In many epidemiological models for paratuberculosis, it is assumed that infected young stock (<2 years of age) do not shed Mycobacterium avium subsp. paratuberculosis (MAP) before adulthood. If this assumption were true, the effective separation of young stock from adult cattle (≥ 2 years) would largely prevent postnatal infections, provided that uninfected adult cattle are highly resistant to infection. However, this assumption is in contrast with observed faecal shedding of MAP in young stock. Consequently, this assumption may have resulted in an underestimation of the effects of MAP transmission in herds participating in certification-, surveillance-, and control programmes for paratuberculosis. Therefore, the aim of the present study was to evaluate the long-term effects of transmission of MAP amongst young stock on key output parameters of certification-, surveillance-, and control programmes for paratuberculosis in simulated closed dairy herds. Closed Dutch dairy herds participating in a paratuberculosis programme were simulated with a stochastic model, JohneSSim. Various test schemes, preventive management measures, distributions of age at onset of faecal shedding and rates of effective contacts between young stock were simulated. The results indicate that transmission of MAP amongst young stock has no relevant effects on the animal-level prevalence and milk quality of herds that are certified in a paratuberculosis programme. However, transmission of MAP amongst young stock increased the economic losses due to paratuberculosis and costs of participation in a programme. Moreover, it substantially decreased the beneficial effect of the separation of young stock from adult cattle on the probability of being certified. However, even in the presence of transmission of MAP amongst young stock, preventive management measures to separate young stock from adult cattle remain important.

Evaluation of Ziehl-Neelsen stained faecal smear and ELISA as tools for surveillance of clinical paratuberculosis in cattle in the Netherlands.

Testing cattle suspected of clinical paratuberculosis is an important element of surveillance of paratuberculosis. The aim of this study was to evaluate the diagnostic-test characteristics of microscopic examination of Ziehl-Neelsen stained faecal smears for acid-fast Mycobacteria (ZN-test) and serum-ELISA in cattle suspected of clinical paratuberculosis in the Netherlands. Results of all samples submitted for ZN-test and serum-ELISA between April 2003 and April 2006 to our laboratory were retrieved. Results from cattle for which both tests were performed were analysed using two Bayesian latent-class models for evaluation of diagnostic tests in two populations without a gold standard, assuming (a) conditional independence of tests, or (b) conditional dependence of tests in both infected and non-infected cattle. Sampled cattle were divided into two populations in different ways using four known risk factors for clinical paratuberculosis: region, soil type, clinical signs, and age. For 892 cattle suspected of clinical paratuberculosis, both ZN-test and serum-ELISA results were retrieved: 250 ZN-positive and ELISA-positive, 12 ZN-positive and ELISA-negative, 260 ZN-negative and ELISA-positive, and 370 ZN-negative and ELISA-negative cattle. With priors based on the available literature, the posterior estimates of sensitivity, specificity, and positive and negative predictive values of the ELISA were always higher than those of the ZN-test. Furthermore, lower limits of the 95% credibility intervals of the posterior positive predictive values of the ELISA were >or=99.7%, and of the negative predictive values of the ELISA >or=56.4%. We conclude that the ELISA is preferred to the ZN-test to confirm the presumptive diagnosis of clinical paratuberculosis in the Netherlands. Little diagnostic information can be gained by performing the ZN-test in addition to the ELISA.

Histamine and methacholine aerosol bronchial challenge in awake guinea pigs.

Cardiopulmonary responses to histamine and methacholine aerosol challenge were examined and compared in unanesthetized spontaneously breathing guinea pigs. All animals had surgically implanted intrapleural catheters and some had arterial or right heart catheters as well. Animals were placed in plethysmographs and exposed to ascending doses of aerosolized agonists. The provocative dose, i.e., the dose that caused a clear bronchospastic response, was defined as the concentration that increased intrapleural pressure to at least 20 cm H2O. Results showed that bronchospasm was characterized further by decreases in dynamic lung compliance and arterial PO2 and an increase in airway resistance. The accumulation of trapped gas in the lung, after challenge, measured in the excised collapsed lung correlated with the increase in intrapleural pressure and with the fall in lung compliance. Male guinea pigs between 3- and 15-weeks of age did not vary in sensitivity to histamine. Methacholine and histamine were equipotent and produced similar responses. Tachyphylaxis was not demonstrated for either compound. In addition, the provocative dose for the drugs remained stable on a day-to-day basis. These results offer insight into the nature of the bronchospastic response in guinea pigs and provide new data on response to methacholine.

Measurements of cardiopulmonary response in awake rats during acute exposure to near-ambient concentrations of ozone.

Cardiopulmonary responses during acute exposure to near-ambient (less than or equal to 1.0 ppm) concentrations of ozone (O3) have not been reported for the unanesthetized rat. Such data on species sensitivity are crucial for the extrapolation of animal data to man. Therefore, this study was conducted to obtain functional measurements on awake rats using head-out plethysmographs and intrapleural or carotid artery catheters during a 135-min exposure to 0.0, 0.12, 0.25, 0.5 or 1.0 ppm O3. Carbon dioxide was added during alternate 15-min periods of the exposure to increase ventilation, much like the use of exercise in human O3 exposure studies. The results established that frequency of breathing was increased and tidal volume was decreased as a function of both the concentration and the duration of exposure. Breathing mechanics and cardiopulmonary measures were only marginally affected. Differences in the response of individual rats revealed that as O3 concentration increased, the proportion of rats responding and the magnitude of the response was increased. These data indicate that, for similar functional responses, the rat's sensitivity to O3 is comparable to that observed in man.