Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

The ERA-40 re-analysis

ERA-40 is a re-analysis of meteorological observations from September 1957 to August 2002 produced by the European Centre for Medium-Range Weather Forecasts (ECMWF) in collaboration with many institutions. The observing system changed considerably over this re-analysis period, with assimilable data provided by a succession of satellite-borne instruments from the 1970s onwards, supplemented by increasing numbers of observations from aircraft, ocean-buoys and other surface platforms, but with a declining number of radiosonde ascents since the late 1980s. The observations used in ERA-40 were accumulated from many sources. The first part of this paper describes the data acquisition and the principal changes in data type and coverage over the period. It also describes the data assimilation system used for ERA-40. This benefited from many of the changes introduced into operational forecasting since the mid-1990s, when the systems used for the 15-year ECMWF re-analysis (ERA-15) and the National Centers for Environmental Prediction/National Center for Atmospheric Research (NCEP/NCAR) re-analysis were implemented. Several of the improvements are discussed. General aspects of the production of the analyses are also summarized. A number of results indicative of the overall performance of the data assimilation system, and implicitly of the observing system, are presented and discussed. The comparison of background (short-range) forecasts and analyses with observations, the consistency of the global mass budget, the magnitude of differences between analysis and background fields and the accuracy of medium-range forecasts run from the ERA-40 analyses are illustrated. Several results demonstrate the marked improvement that was made to the observing system for the southern hemisphere in the 1970s, particularly towards the end of the decade. In contrast, the synoptic quality of the analysis for the northern hemisphere is sufficient to provide forecasts that remain skilful well into the medium range for all years. Two particular problems are also examined: excessive precipitation over tropical oceans and a too strong Brewer-Dobson circulation, both of which are pronounced in later years. Several other aspects of the quality of the re-analyses revealed by monitoring and validation studies are summarized. Expectations that the second-generation ERA-40 re-analysis would provide products that are better than those from the firstgeneration ERA-15 and NCEP/NCAR re-analyses are found to have been met in most cases. © Royal Meteorological Society, 2005. The contributions of N. A. Rayner and R. W. Saunders are Crown copyright.

Intercomparison of radiative forcing calculations of stratospheric water vapour and contrails

Seven groups have participated in an intercomparison study of calculations of radiative forcing (RF) due to stratospheric water vapour (SWV) and contrails. A combination of detailed radiative transfer schemes and codes for global-scale calculations have been used, as well as a combination of idealized simulations and more realistic global-scale changes in stratospheric water vapour and contrails. Detailed line-by-line codes agree within about 15 % for longwave (LW) and shortwave (SW) RF, except in one case where the difference is 30 %. Since the LW and SW RF due to contrails and SWV changes are of opposite sign, the differences between the models seen in the individual LW and SW components can be either compensated or strengthened in the net RF, and thus in relative terms uncertainties are much larger for the net RF. Some of the models used for global-scale simulations of changes in SWV and contrails differ substantially in RF from the more detailed radiative transfer schemes. For the global-scale calculations we use a method of weighting the results to calculate a best estimate based on their performance compared to the more detailed radiative transfer schemes in the idealized simulations.

Cross-modal preference acquisition: evaluative conditioning of pictures by affective olfactory and auditory cues

In this research, a cross-model paradigm was chosen to test the hypothesis that affective olfactory and auditory cues paired with neutral visual stimuli bearing no resemblance or logical connection to the affective cues can evoke preference shifts in those stimuli. Neutral visual stimuli of abstract paintings were presented simultaneously with liked and disliked odours and sounds, with neutral-neutral pairings serving as controls. The results confirm previous findings that the affective evaluation of previously neutral visual stimuli shifts in the direction of contingently presented affective auditory stimuli. In addition, this research shows the presence of conditioning with affective odours having no logical connection with the pictures.

Direct radiative effect of aerosols emitted by transport from road, shipping and aviation

Aerosols and their precursors are emitted abundantly by transport activities. Transportation constitutes one of the fastest growing activities and its growth is predicted to increase significantly in the future. Previous studies have estimated the aerosol direct radiative forcing from one transport sub-sector, but only one study to our knowledge estimated the range of radiative forcing from the main aerosol components (sulphate, black carbon (BC) and organic carbon) for the whole transportation sector. In this study, we compare results from two different chemical transport models and three radiation codes under different hypothesis of mixing: internal and external mixing using emission inventories for the year 2000. The main results from this study consist of a positive direct radiative forcing for aerosols emitted by road traffic of +20±11 mW m−2 for an externally mixed aerosol, and of +32±13 mW m−2 when BC is internally mixed. These direct radiative forcings are much higher than the previously published estimate of +3±11 mW m−2. For transport activities from shipping, the net direct aerosol radiative forcing is negative. This forcing is dominated by the contribution of the sulphate. For both an external and an internal mixture, the radiative forcing from shipping is estimated at −26±4 mW m−2. These estimates are in very good agreement with the range of a previously published one (from −46 to −13 mW m−2) but with a much narrower range. By contrast, the direct aerosol forcing from aviation is estimated to be small, and in the range −0.9 to +0.3 mW m−2.

Coronary heart disease risk screening: the community pharmacy Healthy Heart Assessment Service

Objectives We examined the characteristics and CHD risks of people who accessed the free Healthy Heart Assessment (HHA) service operated by a large UK pharmacy chain from August 2004 to April 2006. Methods Associations between participants’ gender, age, and socioeconomics were explored in relation to calculated 10-year CHD risks by cross-tabulation of the data. Specific associations were tested by forming contingency tables and using Pearson chi-square (χ2). Results Data from 8,287 records were analysable; 5,377 were at low and 2,910 at moderate-to-high CHD risk. The likelihood of moderate-to-high risk for a male versus female participant was significantly higher with a relative risk ratio (RRR) 1.72 (P < 0.001). A higher percentage of those in socioeconomic categories ‘constrained by circumstances’ (RRR 1.15; P < 0.05) and ‘blue collar communities’ (RRR 1.13; P < 0.05) were assessed with moderate-to-high risk compared to those in ‘prospering suburbs’. Conclusions People from ‘hard-to-reach’ sectors of the population, men and people from less advantaged communities, accessed the HHA service and were more likely to return moderate-to-high CHD risk. Pharmacists prioritised provision of lifestyle information above the sale of a product. Our study supports the notion that pharmacies can serve as suitable environments for the delivery of similar screening services.

How was patient empowerment portrayed in information leaflets describing the community pharmacy Medicines Use Review service in the UK?

Objective The Medicines Use Review (MUR) community pharmacy service was introduced in 2005 to enhance patient empowerment but the service has not been taken up as widely as expected. We investigated the depiction of the patient–pharmacist power relationship within MUR patient information leaflets. Methods We identified 11 MUR leaflets including the official Department of Health MUR booklet and through discourse analysis examined the way language and imagery had been used to symbolise and give meaning to the MUR service, especially the portrayal of the patient–pharmacist interactions and the implied power relations. Results A variety of terminology was used to describe the MUR, a service that aimed ultimately to produce more informed patients through the information imparted by knowledgeable, skilled pharmacists. Conclusion The educational role of the MUR overshadowed the intended patient empowerment that would take place with a true concordance-centred approach. Although patient empowerment was implied, this was within the boundaries of the biomedical model with the pharmacist as the expert provider of medicines information. Practice implications If patient empowerment is to be conveyed this needs to be communicated to patients through consistent use of language and imagery that portrays the inclusivity intended.

What is the new medicines use review ‘patient survey’ attempting to capture in the context of existing patient satisfaction with pharmacy questionnaires and a new conceptual framework?

The community pharmacy service medicines use review (MUR) was introduced in 2005 ‘to improve patient knowledge, concordance and use of medicines’ through a private patient–pharmacist consultation. The MUR presents a fundamental change in community pharmacy service provision. While traditionally pharmacists are dispensers of medicines and providers of medicines advice, and patients as recipients, the MUR considers pharmacists providing consultation-type activities and patients as active participants. The MUR facilitates a two-way discussion about medicines use. Traditional patient–pharmacist behaviours transform into a new set of behaviours involving the booking of appointments, consultation processes and form completion, and the physical environment of the patient–pharmacist interaction moves from the traditional setting of the dispensary and medicines counter to a private consultation room. Thus, the new service challenges traditional identities and behaviours of the patient and the pharmacist as well as the environment in which the interaction takes place. In 2008, the UK government concluded there is at present too much emphasis on the quantity of MURs rather than on their quality.[1] A number of plans to remedy the perceived imbalance included a suggestion to reward ‘health outcomes’ achieved, with calls for a more focussed and scientific approach to the evaluation of pharmacy services using outcomes research. Specifically, the UK government set out the main principal research areas for the evaluation of pharmacy services to include ‘patient and public perceptions and satisfaction’as well as ‘impact on care and outcomes’. A limited number of ‘patient satisfaction with pharmacy services’ type questionnaires are available, of varying quality, measuring dimensions relating to pharmacists’ technical competence, behavioural impressions and general satisfaction. For example, an often cited paper by Larson[2] uses two factors to measure satisfaction, namely ‘friendly explanation’ and ‘managing therapy’; the factors are highly interrelated and the questions somewhat awkwardly phrased, but more importantly, we believe the questionnaire excludes some specific domains unique to the MUR. By conducting patient interviews with recent MUR recipients, we have been working to identify relevant concepts and develop a conceptual framework to inform item development for a Patient Reported Outcome Measure questionnaire bespoke to the MUR. We note with interest the recent launch of a multidisciplinary audit template by the Royal Pharmaceutical Society of Great Britain (RPSGB) in an attempt to review the effectiveness of MURs and improve their quality.[3] This template includes an MUR ‘patient survey’. We will discuss this ‘patient survey’ in light of our work and existing patient satisfaction with pharmacy questionnaires, outlining a new conceptual framework as a basis for measuring patient satisfaction with the MUR. Ethical approval for the study was obtained from the NHS Surrey Research Ethics Committee on 2 June 2008. References 1. Department of Health (2008). Pharmacy in England: Building on Strengths – Delivering the Future. London: HMSO. www. official-documents.gov.uk/document/cm73/7341/7341.pdf (accessed 29 September 2009). 2. Larson LN et al. Patient satisfaction with pharmaceutical care: update of a validated instrument. JAmPharmAssoc 2002; 42: 44–50. 3. Royal Pharmaceutical Society of Great Britain (2009). Pharmacy Medicines Use Review – Patient Audit. London: RPSGB. http:// qi4pd.org.uk/index.php/Medicines-Use-Review-Patient-Audit. html (accessed 29 September 2009).

A retrospective audit of medicines use review forms

The medicines use review (MUR) service was introduced in England and Wales in 2005 to improve patients’ knowledge and use of medicines through a private, patient–pharmacist consultation. The pharmacist completes a standard form as a record of the MUR consultation and the patient receives a copy. The 2008 White Paper, Pharmacy in England[1] notes some MURs are of poor or questionable quality and there are anecdotal reports that pharmacists elect to conduct ‘easy’ MURs with patients on a single prescribed medicine only.[2] In 2009, the Royal Pharmaceutical Society of Great Britain (RPSGB) launched a multi-disciplinary audit template to review the effectiveness of MURs and improve their quality.[3] Prior to this, we conducted a retrospective MUR audit in a 1-month period in 2008. Our aims were to report on findings from this audit and the validity of using MUR forms as data for audit.

How is the language of medicines use review leaflets symbolising the service?

Introduction The medicines use review (MUR), a new community pharmacy ‘service’, was launched in England and Wales to improve patients’ knowledge and use of medicines through a private, patient–pharmacist appointment. After 18 months, only 30% of pharmacies are providing MURs; at an average of 120 per annum (maximum 400 allowed).1 One reason linked to low delivery is patient recruitment.2 Our aim was to examine how the MUR is symbolised and given meaning via printed patient information, and potential implications. Method The language of 10 MUR patient leaflets, including the NHS booklet,3 and leaflets from multiples and wholesalers was evaluated by discourse analysis. Results and Discussion Before experiencing MURs, patients conceivably ‘categorise’ relationships with pharmacists based on traditional interactions.4 Yet none of the leaflets explicitly describe the MUR as ‘new’ and presuppose patients would become involved in activities outside of their pre-existing relationship with pharmacists such as appointments, self-completion of charts, and pharmacy action plans. The MUR process is described inconsistently, with interchangeable use of formal (‘review meeting‘) and informal (‘friendly’) terminology, the latter presumably to portray an intended ‘negotiation model’ of interaction.5 Assumptions exist about attitudes (‘not understanding’; ‘problems’) that might lead patients to an appointment. However, research has identified a multitude of reasons why patients choose (or not) to consult practitioners,6 and marketing of MURs should also consider other barriers. For example, it may be prudent to remove time limits to avoid implying patients might not be listened to fully, during what is for them an additional practitioner consultation.

Uptake of a free coronary heart disease risk screening programme in community pharmacy: the Healthy Heart Assessment service

Introduction Health promotion (HP) aims to enhance good health while preventing ill-health at three levels of activity; primary (preventative), secondary (diagnostic) and tertiary (management).1 It can range from simple provision of health education to ongoing support, but the effectiveness of HP is ultimately dependent on its ability to influence change. HP as part of the Community Pharmacy Contract (CPC) aims to increase public knowledge and target ‘hard-to-reach’ individuals by focusing mainly on primary and tertiary HP. The CPC does not include screening programmes (secondary HP) as a service. Coronary heart disease (CHD) is a significant cause of morbidity and mortality in the UK. While there is evidence to support the effectiveness of some community pharmacy HP strategies in CHD, there is paucity of research in relation to screening services.2 Against this background, Alliance Pharmacy introduced a free CHD risk screening programme to provide tailored HP advice as part of a participant–pharmacist consultation. The aim of this study is to report on the CHD risk levels of participants and to provide a qualitative indication of consultation outcomes. Methods Case records for 12 733 people who accessed a free CHD risk screening service between August 2004 and April 2006 offered at 217 community pharmacies were obtained. The service involved initial self-completion of the Healthy Heart Assessment (HHA) form and measurement of height, weight, body mass index, blood pressure, total cholesterol and highdensity lipoprotein levels by pharmacists to calculate CHD risk.3 Action taken by pharmacists (lifestyle advice, statin recommendation or general practitioner (GP) referral) and qualitative statements of advice were recorded, and a copy provided to the participants. The service did not include follow-up of participants. All participants consented to taking part in evaluations of the service. Ethical committee scrutiny was not required for this service development evaluation. Results Case records for 10 035 participants (3658 male) were evaluable; 5730 (57%) were at low CHD risk (<15%); 3636 (36%) at moderate-to-high CHD risk (≥15%); and 669 (7%) had existing heart disease. A significantly higher proportion of male (48% versus 30% female) participants were at moderate- to-high risk of CHD (chi-square test; P < 0.005). A range of outcomes resulted from consultations. Lifestyle advice was provided irrespective of participants’ CHD risk or existing disease. In the moderate-to-high-risk group, of which 52% received prescribed medication, lifestyle advice was recorded for 62%, 16% were referred and 34% were advised to have a re-assessment. Statin recommendations were made in 1% of all cases. There was evidence of supportive and motivational statements in the advice recorded. Discussion Pharmacists were able to identify individuals’ level of CHD risk and provide them with bespoke advice. Identification of at-risk participants did not automatically result in referrals or statin recommendation. One-third of those accessing the screening service had moderate-to-high risk of CHD, a significantly higher proportion of whom were men. It is not known whether these individuals had been previously exposed to HP but presumably by accessing this service they may have contemplated change. As effectiveness of HP advice will depend among other factors on ability to influence change, future consultations may need to explore patients’ attitude towards change in relation to the Trans Theoretical Model4 to better tailor HP advice. The high uptake of the service by those at moderate-to-high CHD risk indicates a need for this type of screening programme in community pharmacy, perhaps specifically to reach men who access medical services less.

Towards an assessment of multiple ecosystem processes and services via functional traits

Managing ecosystems to ensure the provision of multiple ecosystem services is a key challenge for applied ecology. Functional traits are receiving increasing attention as the main ecological attributes by which different organisms and biological communities influence ecosystem services through their effects on underlying ecosystem processes. Here we synthesize concepts and empirical evidence on linkages between functional traits and ecosystem services across different trophic levels. Most of the 247 studies reviewed considered plants and soil invertebrates, but quantitative trait–service associations have been documented for a range of organisms and ecosystems, illustrating the wide applicability of the trait approach. Within each trophic level, specific processes are affected by a combination of traits while particular key traits are simultaneously involved in the control of multiple processes. These multiple associations between traits and ecosystem processes can help to identify predictable trait–service clusters that depend on several trophic levels, such as clusters of traits of plants and soil organisms that underlie nutrient cycling, herbivory, and fodder and fibre production. We propose that the assessment of trait–service clusters will represent a crucial step in ecosystem service monitoring and in balancing the delivery of multiple, and sometimes conflicting, services in ecosystem management.

Evolutionary bi-stability in pathogen transmission mode

Many pathogens transmit to new hosts by both infection (horizontal transmission) and transfer to the infected host's offspring (vertical transmission). These two transmission modes require speci®c adap- tations of the pathogen that can be mutually exclusive, resulting in a trade-off between horizontal and vertical transmission. We show that in mathematical models such trade-offs can lead to the simultaneous existence of two evolutionary stable states (evolutionary bi-stability) of allocation of resources to the two modes of transmission. We also show that jumping between evolutionary stable states can be induced by gradual environmental changes. Using quantitative PCR-based estimates of abundance in seed and vege- tative parts, we show that the pathogen of wheat, Phaeosphaeria nodorum, has jumped between two distinct states of transmission mode twice in the past 160 years, which, based on published evidence, we interpret as adaptation to environmental change. The ®nding of evolutionary bi-stability has impli- cations for human, animal and other plant diseases. An ill-judged change in a disease control programme could cause the pathogen to evolve a new, and possibly more damaging, combination of transmission modes. Similarly, environmental changes can shift the balance between transmission modes, with adverse effects on human, animal and plant health.