Health Products Safety Research Articles

Les hémolyses retardées post-transfusionnelles chez les patients drépanocytaires : un nouveau défi pour le réseau d’hémovigilance

Delayed hemolytic reaction transfusion in patients with sickle cell disease (SCD) is a serious and still under diagnosed event. Clinical and biological presentation mimics an acute SCD complication. It is a life-threatening event, especially in hyperhemolysis syndrome (HS) characterized by a massive destruction of both the donor's and patient's red blood cells. The main cause is related to the presence of alloantibodies directed against red blood cell antigens, more rarely autoantibodies. In approximately a third of the cases, no new antibody is highlighted. Pathophysiological hypotheses are still under debate but most of the authors agree on the role played by the SCD inflammatory state. Several therapeutic approaches are used but the data are still insufficient to estimate their efficiency. It is admitted that a new transfusion may exacerbate the phenomenon and the benefit–risk of any transfusion must be carefully evaluated. Measures limiting alloimmunization and rigorous follow-up of SCD patients and their immunohematologic status can prevent some of these accidents. The Hemovigilance network has a role to play in the recognition and the description of this risk. A first analysis realized on the French national Hemovigilance database of the French National Agency for Medicines and Health Products Safety (ANSM) over the period 2000–2013, shows us interesting information but some inadequacies, described here, must be taken into account to strengthen these data and insure in the future a better reporting quality.

Residual risk and retrospective analysis of transfusion-transmitted bacterial infection reported by the French National Hemovigilance Network from 2000 to 2008.

Regarding blood safety, transfusion-transmitted bacterial infection (TTBI) remains the most frequent infectious risk. The incidence of these episodes needs to be assessed and updated frequently to accurately manage this risk. TTBIs were reported by the French network of local correspondents in each hospital and blood center. The regional coordinator managed the investigation. A multidisciplinary expert group from the French National Agency of Medicine and Health Products Safety (ANSM) analyzed each TTBI according to a standardized scale of imputability and severity. Only cases with likely or certain imputability are reported in this study. In France, 18.0 × 10(6) red blood cell (RBC) products, 1.94 × 10(6) platelet concentrates (PCs), and 2.44 × 10(6) fresh-frozen plasma units were transfused throughout 2000 to 2008. The incidence of TTBI was 2.45, 24.7, and 0.39 per million blood components (BCs), PCs, and RBCs, respectively. For PCs, the incidences of severe (vital threat or death) and fatal TTBI were 13.4 and 5.14 per million, respectively. PCs were responsible for 87% of TTBIs. A total of 66.7% of the implicated bacteria were Gram positive, most of them belonging to the normal skin flora. A total of 33.3% of the other implicated bacteria were Gram negative. The French hemovigilance system provides an accurate estimate of the TTBI incidence during a period with diversion and improving skin disinfection but without bacterial detection screening. This tool would be able to evaluate further additional safety procedures like bacterial screening and pathogen reduction technology.

French contribution to develop Prussian blue

Purpose: Prussian blue is an antidote indicated for the treatment of internal cesium radioisotope contamination. The French armed forces develop and manufacture some antidotal drugs meeting regulatory, analytical and pharmaceutical requirements in order to submit marketing authorization documentation. Prior to an initial meeting with the French National Agency for Medicines and Health Products Safety (ANSM) in 2011, the authors were following regulatory developments in free cyanide release, active pharmaceutical ingredient (API) synthesis, API specifications, ability of cesium/Prussian blue binding products and collection of pre-clinical data.Materials and methods: Free cyanide release was assessed by ultraviolet-visible (UV-Vis) spectrometry at 615 nm. The kinetics of cesium were evaluated in vitro by flame atomic absorption. Good laboratory practice (GLP) and mutagenic assays were examined in rat studies to assess ‘no absorption’.Results: A validated method makes it possible to assess the free cyanide in API according to the published tolerability in humans. The French synthesizer meets good manufacturing practice (GMP) to give a drug that is compliant with all specifications, ensuring its high quality. Two standard mutagenic assays showed mutagenic potential, leading to further tests to obtain more information on any induced chromosomal aberrations. Absorption could be an important factor in determining the risk posed by the drug.Conclusion: The French health service provides the country with several antidotal drugs reducing Chemical, Biological, Radiological and Nuclear (CBRN) risks. Using their GMP manufacturing facilities and pharmaceutical expertise, the French armed forces have contributed to developing drugs with marketing authorization, such as pentetate calcium trisodium (Ca-DTPA) for infusion, or under development with the French Alternative Energies and Atomic Energy Commission (CEA), such as Ca-DTPA by inhalation.

French Product Liability Law: Towards a Pro-Plaintiff System

EUROPE is generally regarded as a place where exposure to damages is relatively low and seen as place where cases are decided on their legal merits, without a lot of theater. (1) Unfortunately, some European jurisdictions tend to singularize themselves by drifting away from traditional principles of civil liability. Among those, France has become more and more challenging for manufacturers, its civil liability system becoming as unwelcoming for corporations as its tax and employment regimes. In addition, the past three years in France have been characterized by an increase in the number of warnings against potentially hazardous substances to human health and the environment in consumer products or the workplace. The French public has been targeted by a significant number of headlines that draw attention to scientific reports condemning substances. Media reports have linked alleged dangers to pesticides, diesel particles, GMO, asphalt, phthalates or Bisphenol A, among others. Industry has been slow to react, while plaintiffs' associations, on the other hand, have been quick to emerge and are very active in seeking to obtain bans or limitations from the French government, which in turn is keen on granting them on the precautionary principle. Over the past couple of years, French authorities have been under attack as a result of several health scandals, accused of not taking measures quickly enough. The result is that these same authorities are now (too) proactive in banning substances and imposing new rules on manufacturers. For instance on June 14, 2012, the French National Agency for the Safety of Medicines and Health Products (ANSM) (2) issued a decision requesting the recall and sudden prohibition of cosmetic products containing chloroacetamide. (3) The ANSM explained that this prohibition was a precaution until the European Union (EU) Commission had made a decision on this substance. Less than a year before, the French National Assembly voted against the use of parabens, alkylphenols and phthalates. (4) In the same line, France is one of the first Member States of the EU to ban the use of Bisphenol A in certain children's products, and as of January 1, 2015, in all food packaging. (5) Another exception in France is the vote by the French National Assembly to prohibit a corn GMO manufactured by Monsanto on and after April 15, 2015. Besides the increasing regulatory burden, which can sometimes be fairly unpredictable, the legal regime around potentially hazardous substances has suffered from a change in civil liability and product liability rules. Indeed, the control of the use of potentially hazardous substances seems to be governed by the will of the French authorities and courts to reassure the public no matter what. Historically, product liability arose by case law based on the general law of obligations, in particular, civil tort liability. Liability implied a fault of the manufacturer in the design or manufacture of a product, a loss, usually bodily injury, and a causal link between the fault and the alleged loss. The purpose of liability was to compensate the user for the loss sustained due to the latter's exposure by the manufacturer to an established danger. French case law, as described in this article, has progressively led to a regime of purely objective (strict) liability, through (i) the disappearance of the concept of fault, (ii) the dilution of the causal link, and (iii) an overly favorable regime for plaintiffs concerning the demonstration of their alleged damage. As discussed in Section I with respect to the concept of fault, the disputes relating to the use of asbestos, which involve both liability law and employment law, are particularly topical. Companies are currently required to compensate all sorts of losses relating to asbestos, including for plaintiffs who are perfectly healthy, based on anxiety (which in the United States may be styled emotional distress) that one day they will develop an illness, even though the majority of these companies lawfully used asbestos in their manufacturing sites in full compliance with the rules that were applicable at the time. …

The effect of Cree traditional medicinal teas on the activity of human cytochrome P450-mediated metabolism

Ethnopharmacological relevanceRhododendron groenlandicum (Bog Labrador tea), Rhododendron tomentosum (Marsh Labrador tea) and Juniperus communis (Juniper) are used in medicinal teas by Canadian aboriginal cultures alone and in combination with conventional drug products. The safety of this combination had not been previously examined and this study was initiated to examine the potential of medicinal teas to inhibit the major human drug metabolizing enzyme, cytochrome P450 3A4 (CYP3A4). Materials and methodsThe decoctions of Rhododendron groenlandicum and Rhododendron tomentosum leaves and Juniperus communis berries were examined in a microtiter fluorometric assay to examine their potential to inhibit CYP-mediated metabolism. ResultsThe decoctions showed progressive inhibition towards CYP3A4 the longer the leaves or berries were brewed. R. Rhododendron groenlandicum and Juniperus communis may have the potential to inhibit CYP3A4-mediated metabolism. ConclusionsThe findings of this study with these traditional medicines are significant in that they provide mechanistic support that these products have the potential to affect the safety and efficacy of other health and medicinal products. As this study only examined CYP3A4, it is possible that these medicinals contain substances that could also affect other metabolic enzymes.

Recommandations de l’Agence nationale de sécurité du médicament concernant le traitement de la toux aiguë du nourrisson : évaluation des pratiques médicales dans les Alpes-Maritimes

Guidelines have been published regularly since 2010 by the ANSM (the Health Products Safety Agency) advising against antitussive drugs for infants because of their inefficacy and their side effects (convulsions, respiratory congestion). Antihistamines, mucolytics, and terpene-based suppositories have theoretically disappeared from infant pharmacopoeia. We assessed the degree of compliance with these guidelines on the part of health professionals. From June 2012 to August 2012, 198 general practitioners and 44 pediatricians were assessed in the Alpes-Maritimes department of France by means of questionnaires. At the same time, an analysis of medical prescriptions was sought from the Regional Directorate of Medical Services (RDMS) of the PACA-Corse region Health Insurance. The rate of noncompliance with the contraindications was 14.9% (17.7% general practitioners and 2.3% pediatricians). The RDMS study showed a slight decrease in prescriptions for antitussives not recommended from 2011 to 2012: -21% for pediatricians, -15.5% for generalist physicians. Continued educational and informative campaigns are therefore needed to stop medical prescriptions of cough medicines for infants, which should also involve parents.

French national proficiency testing study for the standardisation of the CFU-GM progenitor assay

The Laboratory Controls Division of the French Health Product Safety Agency (ANSM) had organized annual external quality control (EQC) of Hematopoietic Stem Cells (HSC) preparations from 2000 to 2013. From this experience, it appeared that it was necessary to prepare new technical guidelines for the clonogenic assay. Indeed the present guidelines did not give sufficient tools of validation. The analysis of data collected from the EQC allowed to produce recommendations which have been placed in public inquiry for three months in 2013. In order to evaluate these ones, a Proficiency Testing Study was conducted with 29 control laboratories of HSC. To that end, samples of fresh cord blood, culture medium and cell culture procedure were sent to participants. Three conditions were proposed: seeding 200 cells CD34+ per dish (compulsory requirement) with initial cord blood then according to laboratories practices, seeding at another cell concentration and/or after erythrocyte removal. For the reference condition, coefficients of variation are inferior to 40%, while discrepancies vary much more for the two other conditions (with a maximum value of 116.6%). In order to carry on the assessment of erythrocyte removal procedures initiated during this study, we performed additional testing of sedimentation. They have shown that this simple and fast method can be used with reliability but only in intra-laboratory conditions. Alongside, comments received during the public inquiry were studied. The answers were documented by analyzing data from EQC that showed an improvement of reproducibility of results obtained in 2011-2012. Eventually, the recommendations were adjusted according to our studies and will be evaluated by the Committee of biological products of the French Pharmacopoeia. All our results showing that the clonogenic assay can be used reliably to evaluate the quality of hematopoietic grafts should allow to base the publication of these recommendations in early 2014.

CP-080 Analysis of ondansetron prescription practices in the care of postoperative nausea and vomiting

BackgroundIn 2013, the French Agency for Medicines and Health Products Safety (ANSM) issued recommendations for the use of ondansetron in the context of chemotherapy-induced nausea and vomiting (CINV). They focus...

CP-056 Evaluation of pharmaceutical interventions in a general medical and a geriatric units

Background At Lamentin Hospital Centre in Martinique, prescriptions are analysed by pharmacists in two clinical units, twice a week. This routine analysis leads to pharmaceutical interventions (PIs) defined by the...

PS-051 Risks related to drug recalls: a case report

BackgroundIn case of anomalies or incidents concerning batches of medicine, the ANSM (French Agency for the Safety of Health Products) proceeds to the recall of the affected batches. The recalls...

The external quality assessment schemes for lead in blood organized by the French national agency for medicine and health product safety: a synthesis of 15 years of activity

In 1992, at the request of the French labor ministry following questions on the ability of medical biology laboratories to satisfactorily measure blood lead level (PbB), a national PbB quality control came into being. Only in 1996 did this external quality control include a number of laboratories sufficient to allow for a significant retrospective evaluation. After fifteen years (1996-2011), The French National Agency for Medicines and Health Products Safety wished to exploit the database collected. The number of participating laboratories went down from 73 to 41. On the other hand, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread decrease of the results over the entire range of tested PbBs (9 to 700μg/L). Since 2006, we have observed increasing use of the inductively coupled plasma with mass spectrometry and decreasing use of electrothermal atomic absorption spectrometry. Provided that they rely on identical metrology expertise, the two analytical techniques lead to results on all the tested concentrations that are not statistically different.

Preliminary and ongoing French multicenter prospective naturalistic study of adverse events of antipsychotic treatment in naive children and adolescents.

BackgroundThe prescription of antipsychotics (AP), and especially second generation AP, is increasing worldwide in the pediatric population. Most prescriptions are off-label and despite the identification of frequent and potentially severe adverse events (AE), there are only a few guidelines for the safety management. France is one of the countries with no official safety guidelines.MethodsPsychotropic drug-naive adolescents (13–18 years), hospitalized for an acute psychotic episode and treated with a second-generation antipsychotic were consecutively included in a prospective cohort study. Patients were assessed for their AE at baseline, 2, 6 and 12 weeks after the introduction of drug.ResultsThe majority of patients was treated with risperidone (n = 13), 2 with aripiprazole. The principal findings are: (1) A high incidence of neuromuscular AE: 8/15 muscle weakness, 8/15 extrapyramidal syndrome, 6/15 akathisia, 3/15 oro-facial acute dystonia; (2) Severe catatonia symptoms in 2 patients despite a low to moderate treatment dose, requiring transfer in intensive care unit for one; (3) Weight gain and significant increase of the BMI for all 13 patients who had a 12 weeks follow-up.ConclusionAll adolescents experienced AE, with significant weight gain being observed in all patients who completed the 12-week follow-up. The fact that our patient population was first episode drug naïve may partially explain this observation. Despite the limitation due to the small sample size of this prospective short-term study, such findings are important to report and warrant further research.Clinical and research implicationBecause of the lack of naturalistic follow up studies of antipsychotic treatments in AP-naive children and adolescents and the absence of safety guidelines for the pediatric population in France, we decided to continue our research at a national level. We therefore started a prospective, naturalistic and multicenter study funded by the French National Agency for Medicines and Health Products Safety (ANSM). Study purpose is to evaluate the incidence of adverse events related to antipsychotic drugs in AP-naive children and adolescents. In addition, we aim to provide further evidence for the necessity of national safety guidelines for AP prescription in the pediatric population.

An Update on Zolpidem Abuse and Dependence

In 2004, the health authorities (French National Agency for Medicines and Health Products Safety—ANSM) modified the summary of zolpidem characteristics. Particularly it now includes the sentence “a pharmacodependence may materialize.” The current article aims to show that despite this modification, zolpidem continues to be associated with problematic drug use, as the official system (Center for Evaluation and Information on Pharmacodependence—Addictovigilance network) providing information on the abuse and dependence potential of drugs informs us. The authors reviewed the literature on this topic and analyzed French data from zolpidem's postmarketing period that were collected by the Addictovigilance network from 2003 to 2010. Postmarketing data and the 30 case reports yielded from the literature review highlight a significant dependence and abuse potential for zolpidem. This survey led to propose in stronger additional rules in France to try to mitigate the abuse potential of zolpidem.

PIP breast implant removal: A study of 828 cases

In March, 2010, the French Health Products Safety Agency suspended the sale of prefilled silicone breast implants manufactured by Poly Implants Prosthèse Prothese (PIP) because of a high failure rate and the use of an inappropriate silicone gel that did not comply with CE marking. These findings led to an international medical crisis. In France, 30,000 female patients had PIP implants. In our Department, 1150 PIP breast implants had been implanted in 630 patients since 2001. A retrospective study was conducted to define the rupture rate of these implants and the complications that arise. The women included in the study underwent implant removal from May 2010 to September 2012 for preventive or curative reasons. Data were collected from medical records that included: results of clinical examination, breast ultrasound before removal, rates of implant rupture, results of biopsy of periprosthetic capsule and pericapsule tissue and postoperative complications. A total of 828 PIP breast implants were removed in 455 patients. The rate of ruptured implants was 7.73% (64/828), corresponding to 11.6% of patients. A periprosthetic effusion was associated with rupture in 44% of cases. Breast ultrasound indicated a rupture for 87 implants; 32% were true positives and 3% were false negatives. Periprosthetic capsule biopsy demonstrated the presence of a foreign body, which seemed to be silicone, in 26% of cases and the presence of inflammation in 13% of cases. No siliconoma-type lesion was identified in the pericapsular tissue at biopsy. A total of 14 implants presented perspiration at removal. A statistically significant difference was found between the rates of rupture for texturised implants as compared to the smooth-surfaced implants. There were eight post-revisional-surgery complications (1%) and three cases of breast adenocarcinoma. The preventive explantation of PIP breast implants is justified given the high failure rate (7.73%) and given patients' exposure to silicone gel that did not comply with CE standards in the absence of rupture, through the early perspiration of implants.

Scientific Evidence and Controversies About Pioglitazone and Bladder Cancer: Which Lessons Can Be Drawn?

Pioglitazone, a peroxisome proliferator-activated receptors (PPAR) agonist, has been authorized for the management of type 2 diabetes since 1999 in the US and since 2000 in Europe. Since then, the risk of bladder cancer associated with pioglitazone use has been a serious concern. Following a warning from the Agence Française de Sécurité Sanitaire des Produits de Santé (Afssaps) [the French Agency for the Safety of Health Products], use of pioglitazone was suspended in France and Germany in June 2011. Elsewhere, restrictions on prescriptions were implemented, though for both the European Medicines Agency and the US Food and Drug Administration, the risk-benefit ratio remains favourable. Since the development of pioglitazone, its risk assessment has suffered from several inaccuracies such as its alleged specificity for the male rat, untrustworthy selective agonism for PPARγ and mistaken risk evaluation in the large PROactive trial (PROspective pioglitAzone Clinical Trial In macroVascular Events), where one case with a benign tumour in the placebo group was counted as a cancer case. It took until 2011 for the epidemiological data to be sufficiently numerous and conclusive to initiate application of safety measures. Today, the increased risk of bladder cancer associated with pioglitazone seems to be real, but the absolute risk is relatively low. However, in the context of weak efficacy in an extensive population of patients exposed to pioglitazone, the risk-benefit balance is now difficult to assess, and prescription restrictions do not ensure safety. For future risk management, the authors propose several suggestions, which involve an increasing role of health authorities and academic organizations.

Les 100 médicaments essentiels. Une approche de médecine interne

PurposeUp to 4600 drugs in about 15,000 pharmaceutical forms are available in France which may be a source of misuse with increased occurrence of side effects and costs. While the World Health Organization is encouraging each developed country to work out its own list of essential drugs. The list provided in 2008 by the French Office for the safety of health products has had so far limited impact on practice, so it became obvious to a group of internists to work out a “wise list” of 100 essential medicines covering 95% of the disorders observed in France. MethodsIn June 2011, 10 internists agreed to each provide a list of 100 essential medicines, according to individual experience. In December 2011, a meeting of the participants provided a list as initial consensus and mandated five among them to make proposals for those areas neglected by too many participants or in which needless dispersion of medicines was stated. After internet-facilitated exchanges, an additional list was validated in mild-January 2012. ResultsFifty-four drugs were included in the list of initial consensus (including nine selected by all 10 participants), and 46 in the additional list. So the final “wise list” included 100 drugs. In June 2012, 56 of these drugs were available as generics. This list was compared to those lists set out by five countries in the European Union. ConclusionGenerating such a list is feasible. Undoubtedly still non-comprehensive, this list will benefit from the expertise of 14 general practitioners who are currently working out a similar list across France. The final list will be submitted for validation by the French associations of generalist teachers and Internists.

Analysis of reasons for not implementing pathogen inactivation for platelet concentrates

In the last 10 years three technologies capable of inactivating pathogens in platelet concentrates have been authorized in Europe although only one based on the addition of amotosalen and illumination with ultraviolet A (UVA) light, has been approved by the National Agency for the Safety of Medicines and Health Products (ANSM). An intense debate exists about the implementation of pathogen inactivation technologies for labile blood components in general and for platelet concentrates in particular. In this review, we will analyze some of the most frequently argued reasons for not implementing pathogen inactivation for platelet components, i.e.: current platelet components are safe enough; pathogen inactivation technologies might be toxic for the recipient; and pathogen inactivation technologies affect platelet function and increase the risk of bleeding. The analysis and discussion of the evidence currently available to answer those reservations will be limited to the pathogen inactivation technology based on amotosalen and UVA.

Rupture of Poly Implant Prothèse (PIP) breast implants: experience with the removal of 884 implants

In May of 2010, the French Health Products Safety Agency (AFSSAPS) raised a worldwide alarm about irregularities that had been detected in silicone filled gel mammary implants produced by the company Poly Implant Prothese (PIP). The first report on this matter stated that the manufacturer had changed the gel filled formula and used a medical gel formula that was different from the one authorized by the manufacturing permits. Between November of 2007 and April of 2012, a descriptive, retrospective study was conducted at our center. A total of 443 consecutive patients undergoing an elective PIP implant explant procedure were enrolled, and a total of 884 PIP implants were explanted. These implants had been placed from 2005 to 2010, a period during which a total of 3,002 cohesive silicone gel-filled breast implants manufactured by the French company PIP were implanted. The overall rate of ruptured implants was 10.6 % (94/884), whereas 81.9 % of implants were found to be intact at the time of explantation. The capsular contracture rate was below 1 %. A statistically significant difference was found between the rates of rupture for texturized implants as compared to the smooth-surfaced implants. A rupture rate of 10.6 % was found, which is lower than that reported in another series regarding PIP implants but higher than those reported in series studying prostheses made by other manufacturers. The capsular contracture rate is below 1 % and there is a significantly higher rate of rupture in texturized implants as compared to that in smooth-surfaced ones. In order to avoid future problems, we believe it is important to advise patients to use only implantable medical devices produced in countries with high product control standards.

Updating the French Method for the Causality Assessment of Adverse Drug Reactions

The Imputability Working Group (CRI) updated the French drug reaction causality assessment method. This tripartite group is made up of staff from the French network of regional pharmacovigilance centres, pharmaceutical companies, and the French National Agency for the Safety of Medicines and Health Products (ANSM). After reviewing the strengths and weaknesses of the previous method, several ideas for improvement were proposed: a better-worded and more discriminating scale for certain chronological and semiological criteria, a larger scale for the intrinsic score (increased from 5 to 7 levels), a new bibliographical scale to differentiate between expected and unexpected adverse drug reactions, and a new informativeness scale.

Alteration of the Serum N-glycome of Mice Locally Exposed to High Doses of Ionizing Radiation

Exposure of the skin to ionizing radiation leads to characteristic reactions that will often turn into a pathophysiological process called the cutaneous radiation syndrome. The study of this disorder is crucial to finding diagnostic and prognostic bioindicators of local radiation exposure or radiation effects. It is known that irradiation alters the serum proteome content and potentially post-translationally modifies serum proteins. In this study, we investigated whether localized irradiation of the skin alters the serum glycome. Two-dimensional differential in-gel electrophoresis of serum proteins from a man and from mice exposed to ionizing radiation showed that potential post-translational modification changes occurred following irradiation. Using a large-scale quantitative mass-spectrometry-based glycomic approach, we performed a global analysis of glycan structures of serum proteins from non-irradiated and locally irradiated mice exposed to high doses of γ-rays (20, 40, and 80 Gy). Non-supervised descriptive statistical analyses (principal component analysis) using quantitative glycan structure data allowed us to discriminate between uninjured/slightly injured animals and animals that developed severe lesions. Decisional statistics showed that several glycan families were down-regulated whereas others increased, and that particular structures were statistically significantly changed in the serum of locally irradiated mice. The observed increases in multiantennary N-glycans and in outer branch fucosylation and sialylation were associated with the up-regulation of genes involved in glycosylation in the liver, which is the main producer of serum proteins, and with an increase in the key proinflammatory serum cytokines IL-1β, IL-6, and TNFα, which can regulate the expression of glycosylation genes. Our results suggest for the first time a role of serum protein glycosylation in response to irradiation. These protein-associated glycan structure changes might signal radiation exposure or effects.