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Funding: Dundee Cancer Centre Development Fund. Oncimmune Ltd. and Chief Scientist Office, Scottish Government funded the ECLS Study. Background: The promotion of smoking cessation within lung cancer screening could lead to benefits for smoking-related disease and improve cost-effectiveness of screening. Little is known about how smokers respond to lung cancer screening and how this impacts smoking behaviour. We aimed to understand how lung cancer screening influences individual motivations about smoking, including in those who have stopped smoking since screening. Methods: Thirty one long-term smokers aged 51–74 took part in semi-structured interviews about smoking. They had been screened with the EarlyCDT-Lung Test (13 positive result; 18 negative) as part of the Early Cancer Detection Test Lung Cancer Scotland Study. They were purposively sampled for interview based on their self-reported post-screening smoking behaviour. Eleven participants had stopped smoking since screening. Verbatim interview transcripts were analysed using thematic analysis. Results: Two key overarching themes were interpretations of screening test results and emotional responses to those interpretations. Participants’ understanding of the risk implied by their test result was often inaccurate, for example a negative result interpreted as an ‘all-clear’ from lung cancer and a positive result as meaning lung cancer would definitely develop. Those interpretations led to emotional responses (fear, shock, worry, relief, indifference) influencing motivations about smoking. Other themes included a wake-up call causing changes in perceived risk of smoking-related disease, a feeling that now is the time to stop smoking and family influences. There was no clear pattern in smoking motivations in those who received positive or negative test results. Of those who had stopped smoking, some cited screening experiences as the sole motivation, some cited screening along with other coinciding factors, and others cited non-screening reasons. Cues to change were experienced at different stages of the screening process. Some participants indicated they underwent screening to try and stop smoking, while others expressed little or no desire to stop. Conclusions: We observed complex and individualised motivations about smoking following lung cancer screening. To be most effective, smoking cessation support in this context should explore understanding of screening test results and may need to be highly tailored to individual emotional responses to screening. Publisher PDF

Boron treatment of rats, mice, and dogs has been associated with testicular toxicity, characterized by inhibited spermiation at lower dose levels and a reduction in epididymal sperm count at higher dose levels. The no-adverse-effect level for reproductive effects in male rats is 17.5mg B/kg bw/day. Earlier studies in human workers and populations have not identified adverse effects of boron exposure on fertility, but outcome measures in these studies were relatively insensitive, based mainly on family size and did not include an evaluation of semen end points. A recent study of nearly 1000 men working in boron (B) mining or processing in Liaoning province in northeast China has been published in several Chinese and a few English language papers. This study included individual assessment of boron exposure, interview data on reproductive experience and semen analysis. Employed men living in the same community and in a remote community were used as controls. Boron workers (n=75) had a mean daily boron intake of 31.3mg B/day, and a subset of 16 of these men, employed at a plant where there was heavy boron contamination of the water supply, had an estimated mean daily boron intake of 125 mg B/day. Estimates of mean daily boron intake in local community and remote background controls were 4.25mg B/day and 1.40 mg/day, respectively. Reproductive outcomes in the wives of 945 boron workers were not significantly different from outcomes in the wives of 249 background control men after adjustment for potential confounders. There were no statistically significant differences in semen characteristics between exposure groups, including in the highly exposed subset, except that sperm Y:X ratio was reduced in boron workers. Within exposure groups the Y:X ratio did not correlate with the boron concentration in blood, semen and urine. In conclusion, while boron has been shown to adversely affect male reproduction in laboratory animals, there is no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers.

A prospective study was carried out to investigate the outcome of pregnancy in 300 women who had self-administered an overdose of paracetamol, either alone, or as part of a combined preparation. Exposure occurred in all trimesters. The most striking feature of this study is that the majority of the pregnancies had normal outcomes. Over half of the mothers (160 = 53%) required treatment for the overdose, and 49 of these had specific antidotes (33 mothers had acetylcysteine and 16 mothers had methionine). The rest of the mothers were given nonspecific treatments including ipecacuanha (52), gastric lavage (42), and charcoal (16). None of the mothers died. There were 219 liveborn infants with no malformations, 61 of whom had been exposed in the first trimester. Eleven liveborn infants had malformations; none was exposed in the first trimester. On other infant exposed at 18 weeks had a diaphragmatic hernia; this pregnancy was terminated at 22 weeks. In none of these 12 infants can the malformations be directly associated with paracetamol exposure. There were no apparent differences either in the sex ratio or the body weights of term infants. There were seven full-term infants with neonatal problems that seem unrelated to paracetamol exposure. Six premature infants also had neonatal problems, which were more likely to be related to their degree of prematurity rather than paracetamol exposure. There was no obvious relationship between the time of exposure and the time of delivery. The overall conclusion is that paracetamol overdose per se is not an indication for termination of pregnancy.

The World Health Organisation is attempting to harmonise the processes of risk assessment worldwide in the hope that assessments performed in one country will be acceptable to other countries. This would reduce not only duplication of work by scientists, but would also reduce to a minimum the need for animal studies. There are differences in the scientific approaches used in different countries to the process of hazard and risk assessment. For example, in the USA risk assessment is focusing on development of mathematical models to describe dose-response relationships to define, for example, a benchmark dose. In Europe much less use is made of such models. More dependence is placed on no-effect levels, and the use of safety factors is much more highly developed. Political considerations come into play when one looks at the use, or misuse, that may be made of such hazard and risk assessments. Once a chemical has been classified and placed on a 'list' of reprotoxic chemicals, the underlying criteria may be ignored and actions taken which are quite unjustified by the original scientific evidence.

Background Safety data regarding exposure to artemisinin-based combination therapy in pregnancy are limited. This prospective cohort study conducted in Zambia evaluated the safety of artemether-lumefantrine (AL) in pregnant women with malaria. Methods Pregnant women attending antenatal clinics were assigned to groups based on the drug used to treat their most recent malaria episode (AL vs. sulphadoxine-pyrimethamine, SP). Safety was assessed using standard and pregnancy-specific parameters. Post-delivery follow-up was six weeks for mothers and 12 months for live births. Primary outcome was perinatal mortality (stillbirth or neonatal death within seven days after birth). Results Data from 1,001 pregnant women (AL n = 495; SP n = 506) and 933 newborns (AL n = 466; SP n = 467) showed: perinatal mortality (AL 4.2%; SP 5.0%), comprised of early neonatal mortality (each group 2.3%), stillbirths (AL 1.9%; SP 2.7%); preterm deliveries (AL 14.1%; SP 17.4% of foetuses); and gestational age-adjusted low birth weight (AL 9.0%; SP 7.7%). Infant birth defect incidence was 1.8% AL and 1.6% SP, excluding umbilical hernia. Abortions prior to antenatal care could not be determined: abortion occurred in 4.5% of women treated with AL during their first trimester; none were reported in the 133 women exposed to SP and/or quinine during their first trimester. Overall development (including neurological assessment) was similar in both groups. Conclusions These data suggest that exposure to AL in pregnancy, including first trimester, is not associated with particular safety risks in terms of perinatal mortality, malformations, or developmental impairment. However, more data are required on AL use during the first trimester.

Meeker et al. (2008) reported on associations between blood levels of nine different metals and four aspects of semen quality found in 219 volunteers attending two infertility clinics. Based on the title of their article, it seems that the authors claimed to have found evidence that molybdenum is a male reproductive toxicant. But how robust is the evidence? Meeker et al. (2008) had no primary prior hypotheses, and their study was essentially a “fishing expedition” involving many statistical tests of many possible associations. The authors (Meeker et al. 2008) did note that “some [findings] may be chance findings because of the number of comparisons that were made.” A much stronger statement is appropriate, namely, that it is very likely that some of the findings were chance findings. The overwhelming majority of study subjects (70%) had blood Mo levels below the study limit of detection of 1 μg/L. If a more sensitive assay method had been used [e.g., the method of Case et al. (2001) with a detection limit of 0.06 μg/L], then a better grouping of subjects could have been used in the data analyses. We also believe the authors made an inappropriate analytical decision. In Table 3 of their article, Meeker et al. (2008) summarized analyses in which dose-dependent associations for each metal were considered in turn while adjusting for age and current smoking. The analysis of associations between Mo concentrations and semen motility were based on data from 147 subjects. The assumption appears to be that 72 (219 – 147) subjects had no useful information to provide on the Mo/sperm motility issue. It would have been more scientifically rigorous to allow the analysis of each semen parameter to make use of data from all study subjects, and not just for the sake of completeness. The current approach has introduced bias into the analysis, because different standards are applied to cases [subjects with the adverse health outcome of interest (e.g. poor sperm concentration)] and controls or referents (subjects without the adverse health outcome). To be concrete, in the analyses of sperm concentrations, cases were allowed to have poor sperm motility, whereas controls were not. The effect of this, in practice, is to load the controls with subjects on high incomes who have never smoked. A more standard analysis involving all study subjects in the analysis of each aspect of sperm quality should have been carried out. Such an analysis would likely have provided very different results to the subset analyses they reported. In commenting on the linear regression analyses shown in their Table 4, Meeker et al. (2008) stated that the Mo groups “were associated with suggestive decreasing trends in sperm concentration and morphology.” However, examination of the table shows that neither of the regression coefficients was significantly different from zero (i.e., the blood Mo level had no significant influence on any of the semen quality parameters). Additional studies would be needed to investigate possible effects in semen quality based on much larger population samples containing a wider range of blood Mo levels.

Diagnostic echocardiography has poor access for patients with suspected heart failure. Pre-echocardiography screening with electrocardiograms (ECGs) is recommended as a means of targeting this scarce resource. There are data to support this policy when ECGs are interpreted by cardiologists but not by GPs.To assess the value of GP-reported ECGs as a pre-echocardiography screening test for left ventricular systolic dysfunction (LVSD).Cross-sectional study of GPs' ECG reporting skills.General practice, NHS in Scotland.A randomly selected, stratified sample of 123 Scottish GPs reviewed 180 ECGs (100 abnormal, 50 normal and 30 duplicate) from 150 patients with suspected heart failure. Forty-one patients had LVSD on echocardiography. GPs were required to categorise ECGs as normal or abnormal.Mean sensitivity was 0.94 (95% CI = 0.92 to 0.95). Mean specificity 0.58 (95% CI = 0.56 to 0.60). Mean positive predictive value (PPV) was 0.47 (95% CI = 0.46 to 0.48). Mean negative predictive value (NPV) was 0.96 (95% CI = 0.95 to 0.97). Mean likelihood ratio was 2.39 (95% CI = 2.28 to 2.50). Seventy of 123 (57%) GPs achieved sensitivity of 0.9 and specificity of 0.5 for the detection of LVSD.Most Scottish GPs have the skills to perform pre-echocardiography screening ECGs in patients with suspected LVSD. However, differences in ECG reporting performance between individual GPs will result in widely varying referral rates for echocardiography and differences in the detection rate of LVSD. The implications of these findings need to be considered when heart failure diagnostic services are being developed.

CONCLUSION REGARDING CLASSIFICATION OF GLUFOSINATE-AMMONIUM: Science Partners' Evaluation Group (Evaluation Group) has conducted an independent analysis of the herbicide glufosinate-ammonium (GA) relative to its potential to cause reproductive toxicity in humans. Further, the Evaluation Group has evaluated the implementation of Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC) and Council Directive 91/414/EEC, with respect to classification of chemicals posing potential reproductive hazards. After consideration of all information available to us relevant to the potential of glufosinate-ammonium (GA) to cause reproductive toxicity, the Science Partners Evaluation Group concludes that no classification of GA is justified. The following form the basis of this conclusion. There are no human data to suggest that GA causes reproductive toxicity in women or in their conceptus. The issue concerning possible reproductive hazard to humans is raised solely on the basis of positive animal test results that show GA to cause preimplantation or implantation losses in rats. SPECIFICALLY: a. Daily treatment with GA had no detectable effect on the earliest stages of the reproductive sequence including gametogenesis, ovulation, mating and conception; b. Treatment with GA interfered with rat gestation before and at the stage when the conceptus implants into the uterus. This effect occurred at doses of 360 ppm in the feed (corresponding to daily doses of 27.8 mg/kg bw) and above; and c. After implantation, no further effect of GA on prenatal and post-natal development was recognized. Previous concerns that GA might be toxic to embryonic stages after implantation were not supported by the data. Abortions and stillbirth seen were associated with, and regarded as secondary to, maternal toxicity. There was no evidence suggesting the induction of malformations in the offspring. The mechanism underlying this adverse effect in experimental laboratory animals is identified-inhibition of glutamine synthetase. Glutamine is essential to the viability of the embryo. The embryo is dependent on a maternal source of the amino acid. For embryo lethality to occur, a significant reduction of maternal glutamine is required. Such reduction in maternal glutamine depends on a significant inhibition of glutamine synthetase by GA. This can only occur when the mother is exposed to very high levels of GA. SPECIFICALLY: a. The reproductive toxicity of GA is confined to very short, early stages of reproduction, during which the conceptus is dependent on maternal glutamine; and b. In order for the effect to occur, significant reduction in maternal blood glutamine level is required, which in turn depends on a significant inhibition of glutamine synthetase, induced by high levels of GA in the maternal system. There is no evidence for accumulation of GA in the mammalian organism beyond a factor of two and no evidence for its metabolic toxification. To raise a concern in humans, women would have to be exposed to GA during the very limited time frame of preimplantation or implantation and the exposure would have to be to the exceedingly high levels necessary to alter the maternal metabolism and, correspondingly, result in glutamine levels in maternal tissue and blood plasma being drastically reduced. There is no basis to suggest that such exposures would occur under conditions of normal handling and use. SPECIFICALLY: a. Under conditions of normal handling and use, operators would never be exposed to GA levels that could potentially inhibit glutamine synthetase to the extent that this inhibition could impair preimplantation or implantation. b. All acceptable exposure measurements and predictive calculations confirm this conclusion, and in fact demonstrate that reasonably foreseeable exposure of workers would be to levels significantly below the AOEL. c. The evidence is also clear that there is no reproductive toxicity hazard to workers upon reentry tosprayed fields, bystanders, consumers or toddlers. The safety margin compared to the NOAEL in animal studies is sufficiently large to assure protection of the health of workers using GA as well as bystanders, consumers, and toddlers. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 2 there must be sufficient evidence to produce a strong presumption that human exposure to the substance may result in impaired fertility in humans. It is the conclusion of the Science Partners Evaluation Group that there is no reasonable evidence to suggest a strong presumption of impairment. To the contrary, there is clear evidence demonstrating a strong presumption that exposure to GA would not cause the adverse effect demonstrated in rats. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 3, there must be sufficient evidence to provide a strong suspicion of impaired fertility in humans. There is no basis to conclude that the animal data demonstrating impaired preimplantation or implantation has any relevance to humans in that the effect found in rats only occurs at levels which would never be experienced by workers under conditions of normal handling and use or by bystanders, consumers, or toddlers.

Implementing the evidence base for the management of chronic disease is as challenging as discovering which interventions are effective. The HEARTS collaboration (Heart disease Evidence-based Audit and Research in Tayside Scotland) is achieving that goal for the secondary prevention of coronary heart disease (CHD by linking national databases to manually validated hospital and family practice electronic patient records. Specific data from the system is fed back to practices in a facilitated educational process and through the NHS intranet. This paper describes some of the key features of this strategic decision support system. All residents of the Tayside region of Scotland (n=484,013 mid year estimate 2002) are covered by the system. 9,828 patients who have suffered a myocardial infarction(MI) or who have undergone angioplasty or bypass surgery are registered on the system. Improvements in clinical status and prescribing of effective therapies are 5-10% greater than elsewhere in Scotland.

Many of you have seen me worriedly writing in the corner, sometimes furiously, trying to get down all the very important points that the conference speakers were making. It is now my task to try to sum up this conference and to give you my idea of the implications for human health on the basis of the latest information presented here. There was a wide range of papers, including the chemical and physical prop? erties of the element and its compounds; their uses; the various methods for the analysis of boron in plants, animals, and humans, as well as in air, water and soil; the biochemical and pharmacological effects of boron in plants, animals, and humans; the effects of dietary boron in experimental ani? mals; the effects of boron in human nutri? tion and human physiology; the toxicology of boric acid and borax, including develop? mental and reproductive toxicity; and the assessment of health effects among workers exposed to boric acid and borates in their

Three major factors to be considered in assessing the possible effects on developmental toxicology of excursions above the acceptable daily intake (ADI) are discussed. If maternal toxicity occurs at lower doses than developmental toxicity, then there may be adequate protection for the fetus if the mother is protected. In other cases, the first adverse developmental effects are usually small and reversible changes in fetal weight and it is unlikely that brief excursions, for a few days, above the ADI, would induce changes in final birth weight. The importance of excursions above the ADI on teratogenic responses would likely depend on the mechanism of teratogenesis and whether the agent acted primarily as a result of a high peak plasma level, a Cmax effect, or depended more on the total body exposure, an area under the curve (AUC) effect. This type of information is usually not available from current safety study designs. Finally, the temporal equivalence factors must be taken into account. There are 10- to 100-fold differences in time span for pre- and postnatal development up to sexual maturity, in rodents compared with humans. This can be contrasted with the relatively small pharmacokinetic differences, perhaps of up to 2- or 3-fold in plasma levels of chemicals with the same administered dose in the two species. Thus, single episodes of high chemical exposure have greater opportunity to produce permanent effects on development in rodents compared with humans. The limited evidence from acute poisonings in pregnant women tends to support this hypothesis and it seems unlikely that occasional excursions by women above the ADI would result in developmental toxic effects.

The classification and labeling of dangerous substances was first introduced in 1967 in the European Community with Council Directive 67/548/EEC, known as the Dangerous Substances Directive. The Sixth Amendment to this directive in 1979 introduced a notification procedure for new chemicals and a requirement for labeling chemicals for toxicity. Three special categories for labeling were for carcinogenicity, mutagenicity, and teratogenicity. The teratogenicity classification was restricted to chemicals inducing teratogenic effects in the classical sense of the word, ie, producing only gross structural malformations. Discussions by expert advisors to the European Commission over several years led to a widening of concern in this area of toxicology and, under the recent Seventh Amendment,1 the classification of “teratology” has been changed to “toxic to reproduction.” This includes adverse effects on fertility, pre- and postnatal development, and lactation, and encompasses not only structural but also functional deficits. This will bring about a major change in the testing requirements to allow adequate classification of chemicals for these other aspects of reproductive toxicity.

The classification and labelling of dangerous substances was first introduced in 1967 in the European Community with Council Directive 67/548/EEC known as the Dangerous Substances Directive. The “6th Amendment” to this directive in 1979 introduced a notification procedure and a requirement for labelling chemicals for toxicity. Three special categories for labelling were for “Carcinogenicity, Mutagenicity and Teratogenicity”. The teratogenicity classification was restricted to chemicals inducing “teratogenic” effects in the classical sense of the word ie. producing only gross structural malformations. Discussions by expert advisors to the European Commission over several years has lead to a widening of concern in this area of toxicology and under the forthcoming “7th Amendment” the classification of “Teratology” will be changed to “Toxic to Reproduction”. This will include adverse effects on fertility, pre- and postnatal development and lactation and will encompass not only structural but also functional deficits. This will bring about a major change in the testing requirements to allow adequate classification of chemicals for these other aspects of reproductive toxicity.

Consideration of environmental influences on human reproduction must include an investigation of the socioeconomic factors that play an important role in embryo-fetal development. Nutritional factors are of prime importance, and modern methods of food production and supply have led to new hazards for pregnant women. For example, pregnant women have been advised in a number of European countries not to eat liver due to the very high concentration (frequently exceeding 100,000 IU per 100 g) of vitamin A. The clear demonstration that periconceptional vitamin supplementation can dramatically reduce the recurrence rate of neural tube defects suggests that folic acid deficiency may be common even in otherwise well-nourished women. Modern methods of food production manufacture and sale have increased the risks of Salmonella and Listeria infections in pregnancy. The dangers of social drug use, especially alcohol and tobacco, are discussed. The types of adverse effect that can result from chemical exposure during the different stages of pregnancy is reviewed with a discussion of some of the problems of epidemiological studies in attempting to identify toxic chemicals. The extent of the ignorance concerning the reproductive toxicity of industrial and environmental chemicals is emphasized by the fact that data are available on only a small percentage of even the high-production volume (1000 tons/year) chemicals. The evidence of reproductive toxicity from exposure to lead, methyl mercury, polychlorinated biphenyls, polychlorinated dibenzofurans, and hexachlorobenzene are briefly reviewed. Some areas of research needs are discussed with emphasis on nutrition, food production, preparation, and storage and the new problems that may be introduced by genetic manipulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Progestogens and oestrogens used to maintain pregnancy in cases of threatened abortion could have side-effects on the mother or fetus. The difficulties in interpreting epidemiological studies on the effects of sex hormones on pregnancy are discussed in relation to the combination of hormones employed, their purpose, time of usage and dosage.

Background The absence of robust evidence of safety of medicines in pregnancy, particularly those for major diseases provided by public health programmes in developing countries, has resulted in cautious recommendations on their use. We describe a protocol for a Pregnancy Registry adapted to resource-limited settings aimed at providing evidence on the safety of medicines in pregnancy. Methods/Design Sentinel health facilities are chosen where women come for prenatal care and are likely to come for delivery. Staff capacity is improved to provide better care during the pregnancy, to identify visible birth defects at delivery and refer infants with major anomalies for surgical or clinical evaluation and treatment. Consenting women are enrolled at their first antenatal visit and careful medical, obstetric and drug-exposure histories taken; medical record linkage is encouraged. Enrolled women are followed up prospectively and their histories are updated at each subsequent visit. The enrolled woman is encouraged to deliver at the facility, where she and her baby can be assessed. Discussion In addition to data pooling into a common WHO database, the WHO Pregnancy Registry has three important features: First is the inclusion of pregnant women coming for antenatal care, enabling comparison of birth outcomes of women who have been exposed to a medicine with those who have not. Second is its applicability to resource-poor settings regardless of drug or disease. Third is improvement of reproductive health care during pregnancies and at delivery. Facility delivery enables better health outcomes, timely evaluation and management of the newborn, and the collection of reliable clinical data. The Registry aims to improve maternal and neonatal care and also provide much needed information on the safety of medicines in pregnancy.