Total Cumulative Exposure Research Articles

Auditory effects of multiple underwater impulses on bottlenose dolphins (Tursiops truncatus)

It is becoming increasingly clear that noise may adversely affect the hearing and behavior of many marine mammals, including dolphins and whales. One of the possible consequences of noise exposure is a temporary loss of hearing sensitivity, called a temporary threshold shift (TTS). Previous studies of TTS in marine mammals have used only steady-state and single impulsive sounds; however, many naval, seismic survey, and construction activities generate multiple underwater impulsive sounds. To investigate the auditory effects of multiple underwater impulses, auditory thresholds were measured in bottlenose dolphins before and after exposure to a series of impulses produced by a seismic airgun. Hearing thresholds were compared to determine the amount of TTS as a function of exposure level and the number of impulses. Thresholds were measured by using both psychophysical and auditory evoked potential methods. Preliminary results reveal no measurable TTS after exposure to 10 impulses, with a total cumulative sound exposure level of approximately 195 dB re 1 μPa2 s. [Work supported by the EP Sound and Marine Life Joint Industry Programme.]

PROGNOSIS AND THERAPY WHEN ACUTE PROMYELOCYTIC LEUKEMIA AND OTHER “GOOD RISK” ACUTE MYELOID LEUKEMIAS OCCUR AS A THERAPY-RELATED MYELOID NEOPLASM

Treatment for a pre-existing condition using chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities may lead to the devastating complication of therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML), collectively known as therapy-related myeloid neoplasm (t-MN). This disorder arises as a direct consequence of mutational events induced by the primary treatment. The outcomes for these patients have been historically poor compared to people who develop AML de novo. Currently comprising 10–20% of all cases of AML, t-MN is relatively resistant to conventional leukemia therapies, and is associated with s ort survival times. Median life expectancy from diagnosis is about 8–10 months in most series. Although the spectrum of cytogenetic abnormalities in t-AML is similar to AML de novo, the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-MN. Two distinct groups of patients with t-MN have been described. The more common subtype, seen in about 75% of patients, typically occurs 5–7 years after first exposure to alkylating agents or radiation, is often preceded by a myelodysplastic syndrome (MDS), and is frequently accompanied by clonal cytogenetic abnormalities such as the loss of all or part of chromosomes 5 or 7. Mutations of the P53 tumor suppressor gene are also common. The risk is related to total cumulative exposure over time to alkylating agents. In contrast, among individuals who develop t-AML after treatment with topoisomerase II inhibitors, the latency period to the development of t-AML is often only 1–3 years, antecedent MDS is rare, and gene rearrangements involving MLL at 11q23 or RUNX1/AML1 at 21q22 are common. It is now well recognized that APL and other subtypes of AML with balanced translocations sometimes occur as therapy-related myeloid neoplasms (t-MN) in patients who have previously received cytotoxic therapy or ionizing radiation therapy (RT). The most of this review will focus on these “good risk” leukemias, i.e. those with APL or inv(16)/t(16;16) or t(8;21).

Diagnostic Medical Radiation in Inflammatory Bowel Disease: Primum Non-Nocere?

Introduction Patients with inflammatory bowel disease (IBD) are frequently exposed to diagnostic medical radiation for the diagnosis and evaluation of their disease. Despite increasing awareness of the potentially serious downstream effects, few studies have quantified radiation exposure in IBD patients. Methods We conducted a retrospective review of 220 consecutive patients attending IBD clinics at our hospital. Clinical data including demographics, disease characteristics and therapy were obtained from case note and electronic patient record review. All incidences of diagnostic medical radiation from initial diagnosis until 30 June 2010 inclusive were recorded from case note and computerised radiology database system review. The radiation dose for each procedure was obtained from published tables from the Royal College of Radiologists, UK. Effective dose for each procedure was calculated by multiplying this value by the number of procedures during the study period. The sum of doses received was the cumulative effective dose. Results One hundred and one of the 220 IBD patients reviewed were female, 119 were male. The median age was 48 (range 17–88) and mean disease duration 10 years. One hundred and one patients had Crohn9s disease, 111 patients had ulcerative colitis and 8 patients had an indeterminate colitis. The mean and median cumulative effective radiation doses were 11.61 mSv and 7.21 mSv respectively. A cumulative radiation dose greater than 10 mSv was seen in 41.8% (92) patients and greater than 25 mSv in 13.2% (29) patients. In 9 patients the cumulative effective dose was greater than 50 mSv. Crohn9s disease was associated with a higher cumulative effective dose with exposure exceeding 10 mSv in 62.4%, 25 mSv in 22.8% and 50 mSv in 8.9% patients respectively. CT imaging accounted for 43% and barium studies for 32% of the total cumulative effective dose exposure. Thirty-nine of these patients had small bowel magnetic resonance (MR) studies in the last 2 years as an alternative to ionising radiation procedures. Conclusion Patients with IBD, particularly those with Crohn9s disease are exposed to significant amounts of diagnostic medical radiation in their lifetime. The increased risk of cancer from cumulative radiation coupled with the inherent risk of colorectal malignancy in long standing IBD and the potential for immunomodulator drugs such as azathioprine to increase the risk of cancers (eg lymphoma) is of great clinical and public health concern. Clinicians must remain vigilant to these risks when evaluating these patients and radiation exposure should be minimised and where possible alternatives such as intestinal ultrasound and MR imaging preferred.

Diagnostic medical radiation in inflammatory bowel disease: primum non-nocere?

IntroductionPatients with inflammatory bowel disease (IBD) are frequently exposed to diagnostic medical radiation for the diagnosis and evaluation of their disease. Despite increasing awareness of the potentially serious downstream effects,...

Modeling community asbestos exposure near a vermiculite processing facility: Impact of human activities on cumulative exposure

Contaminated vermiculite ore from Libby, Montana was processed in northeast Minneapolis from 1936 to 1989 in a densely populated urban residential neighborhood, resulting in non-occupational exposure scenarios from plant stack and fugitive emissions as well as from activity-based scenarios associated with use of the waste rock in the surrounding community. The objective of this analysis was to estimate potential cumulative asbestos exposure for all non-occupationally exposed members of this community. Questionnaire data from a neighborhood-exposure assessment ascertained frequency of potential contact with vermiculite processing waste. Monte Carlo simulation was used to develop exposure estimates based on activity-based concentration estimates and contact durations for four scenarios: S1, moved asbestos-contaminated waste; S2, used waste at home, on lawn or garden; S3, installed/removed vermiculite insulation; S4, played in or around waste piles at the plant. The simulation outputs were combined with air-dispersion model results to provide total cumulative asbestos exposure estimates for the cohort. Fiber emissions from the plant were the largest source of exposure for the majority of the cohort, with geometric mean cumulative exposures of 0.02 fibers/cc × month. The addition of S1, S2 and S3 did not significantly increase total cumulative exposure above background exposure estimates obtained from dispersion modeling. Activity-based exposures were a substantial contributor to the upper end of the exposure distribution: 90th percentile S4 exposure estimates are ∼10 times higher than exposures from plant emissions. Pile playing is the strongest source of asbestos exposure in this cohort, with other activity scenarios contributing less than from plant emissions.

Histamine-2 Receptor Antagonist Use and Incident Dementia in an Older Cohort

To examine whether histamine-2 receptor antagonist medications (H2RAs) are associated with a lower incidence of all-cause dementia or Alzheimer's disease (AD), as some studies have suggested. Prospective population-based cohort Group Health, an integrated health maintenance organization, Seattle, Washington. Two thousand nine hundred twenty-three participants aged 65 and older without dementia at baseline, with initial recruitment between 1994 and 1996. Follow-up occurred every 2 years to identify incident dementia and AD using standard criteria. Exposure to H2RAs was determined based on automated pharmacy data. Three aspects of exposure (time-varying) were examined based on standard daily dose (SDD): cumulative use, intensity of use (highest SDD in any prior 2-year window), and cumulative use stratified according to recency (1-3 years vs >3 years before). Over a mean follow-up of 6.7 years, 585 subjects developed dementia (453 developed AD). Total cumulative exposure was not associated with dementia (P=.35; omnibus test) or AD (P=.23). The adjusted hazard ratios for the highest exposure category (>1,080 SDDs) compared with light or no use were 1.28 (95% confidence interval (CI)=0.95-1.72) for dementia and 1.41 (95% CI=1.00-1.97) for AD. Intensity of use was not associated with dementia (P=.39) or AD (P=.63). Examining exposure according to recent and distant cumulative use also showed no association with dementia (P=.11) or AD (P=.30). No association was found between H2RA use and risk of all-cause dementia or AD using more-detailed and -extensive information about past H2RA use than any prior study.

Respiratory symptoms and lung function impairment in underground gold miners in Ghana

This is the first study in Ghana in the Obuasi gold mines where the silica content of the respirable dust is 10%, less than in previously studied gold mines, with only 23% of the miners having ever smoked. The study was to assess the prevalence of respiratory impairment in the Ghanaian gold miner and to quantify the effects of the respirable dust on pulmonary function A cross sectional epidemiological study The study was carried out using MRC respiratory symptoms questionnaire, spirometry, and personal respirable dust measurements. A total of 1236 miners were studied. The mean age was 39.7 +/-5.8 (SD) years with a mean of 12.6 +/- 6.7 (SD) years underground service and a mean total cumulative exposure to dust of 10.34 +/-5.61 (SD) mg.m(-3).years. The prevalence of chronic bronchitis was 21.2% and not clearly related to cumulative exposure. MRC breathlessness grade>/=2 was 31.3%, significantly related to cumulative respirable dust exposure after adjustment of age and smoking. There was however significant reduction in FEF(25-75%) with increasing dust exposure and an interaction with ever smoking. There was no correlation between cumulative exposure to respirable dust and FEV(1) % predicted in any group, suggesting that exposure to respirable silica at a mean level of 0.06 mg/m(3) had no deleterious effect on FEV(1) in a population with little tuberculosis, good housing and a low level of cigarette smoking. The prevalence of chronic bronchitis in the Ghanaian gold mine is related more to smoking than any occupational factors.

Military and Leisure-Time Noise Exposure and Hearing Thresholds of Finnish Conscripts

This study presents an evaluation of the total cumulative noise exposure of Finnish conscripts (N = 416) during military service. All of the conscripts underwent a hearing screening and filled out a noise exposure questionnaire at the beginning and end of their military service. Eighty-nine percent of the conscripts were exposed weekly to military noise of over 85 dBA during the service. Eighteen percent of the conscripts had already reached at the end of their military service a cumulative noise dose corresponding to noise exposure of 85 dB for 40 years. During military service, permanent hearing loss of > 20 dB in the frequency range of 0.5 to 8 kHz increased from 19 to 27% among the conscripts.

Comparison of First, Last, and Longest-Held Jobs as Surrogates for All Jobs in Estimating Cumulative Exposure in Cross-Sectional Studies of Work-Related Asthma

Previous occupational studies have used exposure in most recent job as a surrogate for all jobs or "total work history" exposure. This method may not be valid for diseases in which disability brought on by one job may influence later work history, such as asthma. We investigated different surrogates for total work history for the outcome of asthma symptoms. In a cross-sectional study, we quantitatively compared three exposure surrogates (last job, first job, and longest-held job) with the total cumulative work exposure (all jobs) in a cohort of 1778 aluminium industry workers. The chemical exposures we compared were total fluoride dust, inspirable dust, and sulfur dioxide with the respiratory symptoms of wheeze, chest tightness, and rhinitis. When extrapolated over time, all surrogates quantitatively overestimated the gold standard "all jobs" for all three exposures investigated. For the symptom of wheeze, last job was found to be the worst surrogate for all jobs for the three exposure types investigated. Prevalence ratios for fluoride exposure and the symptom of occupational wheeze were last job 1.07 (95% confidence interval, 0.92-1.26), longest job 1.10 (0.94-1.30), first job 1.14 (0.97-1.35), and all jobs 1.27 (1.05-1.53). Although last job has been found to be a satisfactory surrogate for all jobs in cancer studies, we do not recommend the use of this metric in studies of chronic diseases where development of disability may occur with early exposure. We found that both first job and longest job held were better metrics in studies where the adverse health effect may influence the job history of subject.

Unveiling the broad band X-ray continuum and iron line complex in Mrk 841

Mkr 841 is a bright Seyfert 1 galaxy known to harbor a strong soft excess and a variable K$\alpha$ iron line. It has been observed during 3 different periods by XMM for a total cumulated exposure time of $\sim$108 ks. We present in this paper a broad band spectral analysis of the complete EPIC-pn data sets. We were able to test two different models for the soft excess, a relativistically blurred photoionized reflection (\r model) and a relativistically smeared ionized absorption (\a model). The continuum is modeled by a simple cut-off power law and we also add a neutral reflection. These observations reveal the extreme and puzzling spectral and temporal behaviors of the soft excess and iron line. The 0.5-3 keV soft X-ray flux decreases by a factor 3 between 2001 and 2005 and the line shape appears to be a mixture of broad and narrow components. We succeed in describing this complex broad-band 0.5-10 keV spectral variability using either \r or \a to fit the soft excess. Both models give statistically equivalent results even including simultaneous BeppoSAX data up to 200 keV. Both models are consistent with the presence of remote reflection characterized by a constant narrow component in the data. However they differ in the presence of a broad line component present in \r but not needed in \a. This study also reveals the sporadic presence of relativistically redshifted narrow iron lines.

The origin of the strong soft excess and puzzling iron line complex in Mkn 841

AbstractMkn 841 has been observed during 3 different periods (January 2001, January 2005 and July 2005) by XMM‐Newton for a total cumulated exposure time of ∼108 ks. We present in this paper a broad band spectral analysis of the complete EPIC‐pn data sets. These observations confirm the presence of the strong soft excess and complex iron line profile known to be present in this source since a long time. They also reveal their extreme and puzzling spectral and temporal behaviors. Indeed, the 0.5–2 keV soft X‐ray flux decreases by a factor 3 between 2001 and 2005 and the line shape appears to be a mixed of broad and narrow components, both variable but on different timescales. The broad‐band 0.5–10 keV spectra are well described by a model including a primary power law continuum, a blurred photoionized reflection and a narrow iron line, the blurred reflection fitting self‐consistently the soft excess and the broad line component. The origin and nature of the narrow component is unclear. (© 2006 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Abstract 4163: Higher Dose Exposure of Lovastatin is Not Associated with Adverse Hepatic Outcomes in Patients with Existing Liver Disease

OBJECTIVE: We have previously shown that the rate of subjects developing adverse liver outcomes was substantially lower during lovastatin-exposed periods compared to non-exposed periods in patients with pre-existing liver disease. The objective of this analysis was to estimate the dose-response relationship between differing levels of lovastatin exposure and adverse hepatic outcomes. METHODS: This was a retrospective cohort study. Eligible subjects were adult members of Northern California Kaiser Permanente with at least 2-fold ALT or AST elevations 6–18 months apart, evidence of chronic hepatitis B or C infection, or a diagnosis of a chronic liver disease. Outcomes included the composite of events as well as individual components: liver injury, defined as moderate (3X ULN<ALT<10X ULN) or severe (ALT<10X ULN); development of clinical cirrhosis; liver failure. The dose-response relationships were analyzed by estimating the risk of each outcome in subgroups defined by quartiles of total cumulative lovastatin exposure. Each of these risks was compared to that in the lovastatin-unexposed reference group and a test for trend applied, using orthogonal polynomial contrasts on the coefficients of categorical levels of the exposure variable. RESULTS: 93,106 eligible patients were identified, of whom 15% had been exposed to lovastatin. A strong and monotonic dose-response relationship was found for the composite outcome and moderate liver-injury endpoints. For the composite endpoint, hazard ratios declined from 0.81 in the quartile with least lovastatin exposure to 0.44 in the highest exposed group ( p< .00001). Similarly, for the moderate liver-injury endpoint, hazard ratios declined from 0.97 to 0.27 with increasing lovastatin exposure ( p< .00001). CONCLUSIONS: Among patients with liver disease, lovastatin exposure was associated with a dose-dependent reduction in the risk of several liver-disease outcomes. These results do not support labeling recommendations for avoiding the use of lovastatin at higher doses in patients with liver disease nor the need to closely monitor LFTs during lovastatin treatment.

Estimated Leisure-Time Noise Exposure, Hearing Thresholds, and Hearing Symptoms of Finnish Conscripts

The aim of this study was to set up a statistical measure for determine the total cumulative noise exposure of Finnish conscripts (n = 1,054) as a result of leisure-time noise activities. All of the conscripts underwent hearing screening. The conscripts' time in noisy activities and their rating of the loudness and estimated noise levels of the activities were used as the predictors in the risk analysis. Self-reported hearing symptoms (i.e., tinnitus, pain in the ear) and hearing loss due to noise exposure were also inquired about. Twenty-seven percent of the conscripts had weekly noise exposure to > 85 dBA. Approximately 20% of the conscripts had >20 dB hearing loss in either ear in the frequency range of 0.5 to 8 kHz. The incidence of hearing symptoms seemed to correlate with an increased noise dose.

Multiple senile lentigos of the face, a skin ageing pattern resulting from a life excess of intermittent sun exposure in dark-skinned caucasians: a case-control study

Different patterns of skin ageing can be described depending on the predominant lesions, i.e. wrinkles, laxity, atrophy, senile lentigos (SLs), etc. They may correspond to different epidemiological contexts. To identify and assess the epidemiological factors for a skin ageing pattern characterized by a high density of SLs on the face, or 'lentigo ageing pattern' (LAP). An age- and sex-matched case-control study was conducted in individuals aged between 60 and 80 years, comparing cases (n = 118) with a very high number of SLs on the face for their age, and controls (n = 118) with no or very few SLs for their age. The cases and controls were recruited in two hospitals. In univariate and multivariate analysis, LAP was associated with skin types III and IV, with frequent sunburns, and with the part of the lifetime cumulative sun exposure which was received during vacations. Conversely, there was no link with the occupational and everyday exposures and the total cumulative exposure. LAP was associated with multiple solar lentigos of the upper back. No relationship was found with postmenopausal hormonal therapy, number of naevi, or freckles. Different epidemiological factors may account for the different skin ageing patterns. LAP seems to develop preferentially in dark-skinned caucasians who have repeatedly received intermittent and intense sun irradiations throughout their life, and have often developed solar lentigos on the upper back earlier in life, whereas the 'prominent wrinkling' pattern is known to affect light-skinned people and smokers with a life excess of continuous exposure.

Risk factors of incident melanocytic nevi: A longitudinal study in a cohort of 1,232 young German children

The number of melanocytic nevi is the most important independent risk factor for cutaneous melanoma. Aim of our study was to add information to the controversial discussion on the role of chronic-moderate and intermittent-high sun exposure and sunburns for the development of melanocytic nevi by the use of a large longitudinal study. A longitudinal study with a 3-year follow-up was conducted in 1,232 young children 2-7 years of age attending 78 public nursery schools in Bochum and Stuttgart, Germany. Total body nevus counts, assessment of pigmentary features and nevus counts on arms of parents were carried out. Parents underwent a standardized interview concerning sun exposure, sunburns and sun-protective behavior. Applying multiple linear regression analysis higher numbers of incident nevi were associated with host factors like light skin complexion (skin Type II vs. IV, p = 0.022) and freckling of the face (p < 0.001), with parental factors like nevus counts on mothers' (p < 0.001) and fathers' (p = 0.004) arms and at least one parent being of German descent (p = 0.006), and with environmental factors like intermittent-high sun exposure during holidays (p < 0.001) and chronic-moderate ultraviolet radiation at home (p = 0.007). Sunburns were a significant risk factor for nevus development (p = 0.005). Total cumulative sun exposure seems to be the crucial environmental risk factor for the development of nevi, whether the child is exposed to chronic-moderate or intermittent-high ultraviolet light doses. Public health education should focus primarily on avoiding sun exposure especially in children with fair skin and parents with high nevus counts.

Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors: a case-control study.

A case-control study was undertaken to determine risk factors for lactic acidosis in human immunodeficiency virus-infected patients treated with nucleoside reverse-transcriptase inhibitors (NRTIs). From May 1996 to June 2000, 9 patients with lactic acidosis (defined as a plasma lactic acid level of >5 mM and plasma pH of <7.38) were identified. Control patients were randomly selected from among a large cohort of patients who initiated a dual NRTI regimen in 1996 or after. Two factors were associated with an increased risk of lactic acidosis: first, a creatinine clearance of <70 mL/min before lactic acidosis (OR, 15.8 [range, 3.0-86.5], P<10(-4)), and, second, a low nadir CD4+ T lymphocyte count before the inception of NRTI therapy (OR, 8.4 [range, 1.2-infinity], P=.03). The total cumulative exposure to NRTIs was not associated with an increased risk of lactic acidosis, nor was the cumulative exposure to any of the 4 NRTIs studied. According to these results, monitoring of creatinine clearance, especially in patients with a low nadir CD4+ T lymphocyte count, could lead to modifications in antiretroviral therapy in order to diminish the risk of occurrence of lactic acidosis.

Growth responses of yellow‐poplar(Liriodendron tulipifera L.) exposed to 5 years of O3 aloneor combined with elevated CO2

AbstractField‐grown yellow‐poplar (Liriodendron tulipifera L.) werefumigated from May to October in 1992–96 within open‐topchambers to determine the impact of ozone (O3) aloneor combined with elevated carbon dioxide (CO2) on saplinggrowth. Treatments were replicated three times and included: charcoal‐filteredair (CF); 1 × ambient ozone (1 × O3);1·5 × ambient ozone (1·5 × O3);1·5 × ambient ozone plus 350 p.p.m.carbon dioxide (1·5 × O3 + CO2)(target of 700 p.p.m. CO2); and open‐air chamberlessplot (OA). After five seasons, the total cumulative O3 exposure (SUM00 = sumof hourly O3 concentrations during the study) rangedfrom 145 (CF) to 861 (1·5 × O3) p.p.m. × h (partsper million hour). Ozone had no statistically significant effecton yellow‐poplar growth or biomass, even though total root biomasswas reduced by 13% in the 1·5 × O3‐exposedsaplings relative to CF controls. Although exposure to 1·5 × O3 + CO2 hada stimulatory effect on yearly basal area growth increment aftertwo seasons, significant increases in shoot and root biomass (∼ 60% increaserelative to all others) were not detected until the fifth season.After five seasons, the yearly basal area growth increment of saplingsexposed to 1·5 × O3 + CO2‐air increasedby 41% relative to all others. Based on this multi‐yearstudy, it appears that chronic O3 effects on yellow‐poplargrowth are limited and slow to manifest, and are consistent withprevious studies that show yellow‐poplar growth is not highly responsiveto O3 exposure. In addition, these results show thatenriched CO2 may ameliorate the negative effects of elevatedO3 on yellow‐poplar shoot growth and root biomass underfield conditions.

Nested case-control study of lung cancer in four Chinese tin mines

Objectives: To evaluate the relation between occupational dust exposure and lung cancer in tin mines. This is an update of a previous study of miners with high exposure to dust...

Responses of two birch ( Betula pendula Roth) clones to different ozone profiles with similar AOT40 exposure

Saplings of two clones of European white birch ( Betula pendula Roth) were exposed to three different ozone profiles resulting in same AOT40 value of 13–14 ppm h in a chamber experiment. The sensitive clone 5 and the more tolerant clone 2 were growing (1) under filtered air (=control), or (2) were exposed to 70 ppb ozone for 24 h d −1 (=profile 1), (3) to 100 ppb ozone for 12 h d −1 at 8:00–20:00 (=profile 2), or (4) to 200 ppb ozone for 4.5 h d −1 at 9:30–14:00 (=profile 3) for 20 d. The saplings were determined for growth, visible leaf injuries, stomatal conductance, and concentrations of Rubisco, chlorophyll and carotenoids. Growth responses and induction of visible foliar injuries under different ozone profiles were variable, resulting in 4–17% lower dry mass of shoot, 16–46% reduction in stem height increment and 11–43% increase in visible injuries in clone 5, which was accompanied by higher leaf turnover rate under profile 3 indicating compensation growth. In clone 2, ozone-induced responses ranged from slight stimulation in stem height growth to 13% decrease in dry mass of shoot and 2–16% increase in visible injuries. Daytime stomatal conductance rates were lowered by 14–54% in clone 5 and 9–74% in clone 2, depending on profile. The additional power-weighted analyses revealed that high peak concentrations and exposure shape were important for induction of visible injuries in both clones and reduction in stomatal conductance in clone 5, whereas growth reductions were rather related to total cumulative exposure. The results indicate that profile of ozone exposure, night-time stomatal conductance (24 h flux), and recovery time for defence and compensations reactions should not be ignored in plant response and ozone flux modelling.

Toremifene: where do we stand?

Toremifene is a chlorinated triphenylethylene that is indicated for postmenopausal breast cancer. For advanced disease, toremifene has been found to be as effective and at least as well tolerated as tamoxifen. The same appears to apply for adjuvant setting. After a total cumulative clinical exposure to toremifene of approximately 140 000 patient-years, only 9 cases of endometrial carcinoma have been reported. The annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in breast cancer patients on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo 0.4). Although toremifene (being a partial agonist) may unmask pre-existing endometrial tumours, there is no clinical data implying that it would per se cause endometrial carcinoma.