Correspondence
A statement from Grandjean and Landrigan clearly stating that their addition of fluoride to their list of neurotoxins does not apply to fluoridation at the recommended levels of 0·7–1·2 ppm would clarify our concerns on the misuse and misinterpretation of their paper. We declare no no competing interests.
*Julianna Gelinas, Myron Allukian Jr [email protected] American Association for Community Dental Programs, Nelson Pavilion, Philadelphia, PA 19134, USA (JG, MA) 1
2
3
4
5
6
Grandjean P, Landrigan PJ. Neurobehavioral effects of developmental toxicity. Lancet Neurol 2014; 13: 330–38. Choi AL, Sun G, Zhang Y, Grandjean P. Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect 2012; 120: 1362–68. Whitford GM, Whitford JL, Hobbs SH. Appetitive-based learning in rats: Lack of effect of chronic exposure to fluoride. Neurotoxicol Teratol 2009; 31: 210–15. Shannon FT, Fergusson DM, Horwood LJ. Exposure to fluoridated public water supplies and child health and behaviour. N Z Med J 1986; 99: 416–18. Bazian Ltd. Independent critical appraisal of selected studies reporting an association between fluoride in drinking water and IQ: a report for South Central Strategic Health Authority. London, UK. http://www. fairbanksalaska.us/wp-content/ uploads/2011/07/20090211Bazian-ReviewIQ-Studies.pdf (accessed March 18, 2014). European Union Scientific Committee on Health and Environmental Risks (SCHER). Opinion on critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water. May 16, 2011. http://ec.europa.eu/health/scientific_ committees/environmental_risks/docs/ scher_o_122.pdf (accessed March 18, 2014).
Authors’ response We are grateful for the comments on our review.1 Our aim was to present a balanced assessment based on our best professional judgement concerning toxicity of industrial chemicals to the developing human brain. The diversity of opinion expressed in these letters reflects the serious absence of neurotoxicity information about most chemicals, but we interpret all four letters as supportive of a call for intensified research. Goldstein and Saltmiras echo Monsanto’s oft-repeated defence 648
that glyphosate is a safe herbicide. Still, the toxicity documentation publicly available on this widely used substance is limited. We have been unable to find documentation of any neurotoxicity testing of glyphosate considered valid by the US Environment Protection Agency. Experimental evidence lends support to the likelihood of neurotoxicity.2 On the basis of clinical reports mentioned by Goldstein and Saltmiras, we therefore believe that glyphosate should be considered a neurotoxic hazard. Monsanto’s argument for safety relies on the relative absence of research results rather than on data documenting safety. We agree with Feldman that fluoride is important for children’s oral health. However, the fact that a trace element has beneficial effects at low doses in specific tissues does not negate the possibility that neurotoxicity might also be occurring, especially at increased levels of exposure. Indeed, concerns about fluoride toxicity were already raised by a National Research Council expert committee.3 Feldman describes the recent meta-analysis4 as selective and based on old, confounder-ridden studies. In support of her claims, she refers to two previous reports that reviewed some of the same studies, although without access to important background information. Feldman makes other serious errors—eg, by linking, without justification, a rise in population mean intelligent quotient (IQ) to the introduction of water fluoridation. Similarly, Gelinas and Allukian dispute the validity of previous studies on fluoride exposure and neurobehavioural deficits. We do not deny the importance of a doseresponse relation, which has been a unifying concept in toxicology since the time of Paracelsus. However, as we emphasised in our Review, emerging evidence on developmental neurotoxicity makes it clear that the timing of exposure is also of
great importance, especially during highly vulnerable windows of brain development. Due to the growing evidence on adverse effects, US authorities now recommend that fluoridation of community water should not exceed 0·7 mg/L.5 We agree with Wendroff’s perspective, but have been unable to identify epidemiological support for a claim of developmental neurotoxicity from exposure to mercury vapour. As elemental mercury might soon be added to the list of confirmed developmental neurotoxicants, we support the evidence-informed prevention of mercury exposures suggested by Wendroff. In writing our Review, we have tried to steer a middle course between advocates for particular public-health actions and spokespersons for the chemical industry. We believe that sufficient evidence is already available that industrial chemicals endanger human brain development and that unrestrained production and release of such chemicals are short-sighted, dangerous, unsustainable, and fundamentally immoral. We call for a thorough revision of chemical safety policies and for the establishment of a documentation centre on developmental neurotoxicity modelled after the International Agency for Research on Cancer. We declare no competing interests.
*Philippe Grandjean, Philip J Landrigan [email protected] Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark, and Department of Environmental Health, Harvard School of Public Health, Boston, MA 02215, USA (PG); and Department of Preventive Medicine, Mount Sinai School of Medicine, New York, NY; USA (PJL) 1
2
3
Grandjean P, Landrigan, P.J. Neurobehavioural impact of developmental toxicity. Lancet Neurol 2014; 13: 330–38. Cattani D, de Liz Oliveira Cavalli VL, Heinz Rieg CE, et al. Mechanisms underlying the neurotoxicity induced by glyphosatebased herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity. Toxicology 2014; 320: 34–45. National Research Council (NRC). Fluoride in drinking water: a scientific review of EPA’s standards. Washington, DC: The National Academies Press, 2006.
www.thelancet.com/neurology Vol 13 July 2014
Correspondence
4
5
Choi AL, Sun G, Zhang Y, Grandjean P. Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect 2012; 120: 1362–68. US Environmental Protection Agency. EPA and HHS Announce New Scientific Assessments and Actions on Fluoride. http://yosemite.epa. gov/opa/admpress.nsf/6427a6b7538955c585 257359003f0230/86964af577c37ab2852578 11005a8417!OpenDocument (accessed May 23, 2014).
Evidence or clinical implementation: which should come first? The Editorial1 in the June issue of The Lancet Neurology discusses the clinical potential of the Dutch ParkinsonNet—a multidisciplinary network of professionals that specialises in treatment of patients with Parkinson’s disease. The core of the network consists of allied health and other non-medical professionals who are trained to work according to clinical practice guidelines, who continuously increase their Parkinson’s-specific expertise by treating large caseloads, and who adopt a patient-centred, collaborative approach. The Editorial points to the value of ParkinsonNet for improvement of participatory medicine in clinical practice, but emphasises the need to gather further evidence before this multidisciplinary concept can be implemented in other health-care systems. This view is understandable in most scientific fields, but when multidisciplinary care is assessed, a chicken or egg discussion is at play: should we obtain evidence about multidisciplinary care and then implement it within professional networks; or should we start these networks first, even when little evidence is available, and exploit those networks to obtain the obligatory evidence that either supports or refutes the effectiveness of multidisciplinary care? We favour the latter strategy. It is not possible to obtain robust evidence
www.thelancet.com/neurology Vol 13 July 2014
for non-medical interventions such as physiotherapy or nursing when only inexperienced professionals are available who cannot deliver the intervention properly. Specialised networks such as ParkinsonNet offer the necessary infrastructure for clinical trials. Trained ParkinsonNet experts can deliver experimental interventions consistently, with little variation across practices, and in accordance with guideline recommendations or research protocols. We previously used the ParkinsonNet infrastructure to assess several allied health interventions. The first intervention was tested in a clustercontrolled trial which compared eight regions that had specialised ParkinsonNet physiotherapists with eight regions that had generically trained therapists only.1 ParkinsonNet therapists adhered better to guidelines and offered cheaper care than did generically trained therapists, but their clinical outcomes were comparable to those of usual care. The second intervention was tested in the ParkFit trial, that assessed whether personal coaches can promote a more active lifestyle in sedentary patients with Parkinson’s disease— coaches were specifically trained ParkinsonNet physiotherapists. 3 A third trial tested the effectiveness of occupational therapy, again using specialised ParkinsonNet therapists to deliver the intervention.4 Finally, we have done several studies within ParkinsonNet to assess the merits of integrated multidisciplinary care. We recently reported the results of a controlled, non-randomised trial that compared one region that had both a specialised Parkinson’s disease centre and a regional ParkinsonNet with two control regions that had neither.5 Our analyses showed minor benefits in favour of the integrated care model, but these disappeared after controlling for baseline differences. All these trials would have been impossible if the
network implementation had not preceded the studies. Importantly, the outcomes of these trials can be readily shared with all network participants, allowing for rapid implementation of new knowledge into everyday clinical practice. To disseminate fresh research findings, we increasingly use online communities where ParkinsonNet professionals meet to learn about the latest evidence.6 As such, ParkinsonNet creates an interesting infrastructure for health-care innovation, for high-quality research, and for quick dissemination of new evidence to committed professionals. BRB has received honoraria from sitting on the scientific advisory boards for GlaxoSmithKline, UCB, and Danone, and received research support and grants from The National Parkinson Foundation, the Netherlands Organisation for Scientific Research (NWO), the Michael J Fox Foundation, Prinses Beatrix Spierfonds, Stichting Parkinson Fonds, and Alkemade-Keuls Fonds. For the development of the Dutch ParkinsonNet, BB and MM received grants from ZonMw, Zorgverzekeraars Nederland, Parkinson Vereniging, Stichting Parkinson Nederland, Fonds Nuts Ohra, Prinses Beatrix Fonds, Michael J Fox Foundation, National Parkinson Foundation, Centraal Ziekenfonds (CZ), Stichting Volksgezondheidszorg (VGZ), and Achmea.
*Bastiaan R Bloem, Marten Munneke [email protected] Department of Neurology (935), Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands (BRB, MM) 1 2
3
4
5
6
Consumer choices in Parkison’s disease. Lancet Neurol 2014; 13: 525. Munneke M, Nijkrake MJ, Keus SH, et al. Efficacy of community-based physiotherapy networks for patients with Parkinson’s disease: a cluster-randomised trial. Lancet Neurol 2010; 9: 46–54. van Nimwegen M, Speelman AD, Overeem S, et al. Promotion of physical activity and fitness in sedentary patients with Parkinson’s disease: randomised controlled trial. BMJ 2013; 346: f576. Sturkenboom IH, Graff MJ, Hendriks JC, et al. Effectiveness of occupational therapy for patients with Parkinson’s disease: a randomised controlled trial. Lancet Neurol 2014; 13: 557–66. van der Marck MA, Munneke M, Mulleners W, et al. Integrated multidisciplinary care in Parkinson’s disease: a non-randomised, controlled trial (IMPACT). Lancet Neurol 2013; 12: 947–56. Bloem BR, Munneke M. Revolutionising management of chronic disease: the ParkinsonNet approach. BMJ 2014; 348: g1838.
649
A statement from Grandjean and Landrigan clearly stating that their addition of fluoride to their list of neurotoxins does not apply to fluoridation at the recommended levels of 0·7–1·2 ppm would clarify our concerns on the misuse and misinterpretation of their paper. We declare no no competing interests.
*Julianna Gelinas, Myron Allukian Jr [email protected] American Association for Community Dental Programs, Nelson Pavilion, Philadelphia, PA 19134, USA (JG, MA) 1
2
3
4
5
6
Grandjean P, Landrigan PJ. Neurobehavioral effects of developmental toxicity. Lancet Neurol 2014; 13: 330–38. Choi AL, Sun G, Zhang Y, Grandjean P. Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect 2012; 120: 1362–68. Whitford GM, Whitford JL, Hobbs SH. Appetitive-based learning in rats: Lack of effect of chronic exposure to fluoride. Neurotoxicol Teratol 2009; 31: 210–15. Shannon FT, Fergusson DM, Horwood LJ. Exposure to fluoridated public water supplies and child health and behaviour. N Z Med J 1986; 99: 416–18. Bazian Ltd. Independent critical appraisal of selected studies reporting an association between fluoride in drinking water and IQ: a report for South Central Strategic Health Authority. London, UK. http://www. fairbanksalaska.us/wp-content/ uploads/2011/07/20090211Bazian-ReviewIQ-Studies.pdf (accessed March 18, 2014). European Union Scientific Committee on Health and Environmental Risks (SCHER). Opinion on critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water. May 16, 2011. http://ec.europa.eu/health/scientific_ committees/environmental_risks/docs/ scher_o_122.pdf (accessed March 18, 2014).
Authors’ response We are grateful for the comments on our review.1 Our aim was to present a balanced assessment based on our best professional judgement concerning toxicity of industrial chemicals to the developing human brain. The diversity of opinion expressed in these letters reflects the serious absence of neurotoxicity information about most chemicals, but we interpret all four letters as supportive of a call for intensified research. Goldstein and Saltmiras echo Monsanto’s oft-repeated defence 648
that glyphosate is a safe herbicide. Still, the toxicity documentation publicly available on this widely used substance is limited. We have been unable to find documentation of any neurotoxicity testing of glyphosate considered valid by the US Environment Protection Agency. Experimental evidence lends support to the likelihood of neurotoxicity.2 On the basis of clinical reports mentioned by Goldstein and Saltmiras, we therefore believe that glyphosate should be considered a neurotoxic hazard. Monsanto’s argument for safety relies on the relative absence of research results rather than on data documenting safety. We agree with Feldman that fluoride is important for children’s oral health. However, the fact that a trace element has beneficial effects at low doses in specific tissues does not negate the possibility that neurotoxicity might also be occurring, especially at increased levels of exposure. Indeed, concerns about fluoride toxicity were already raised by a National Research Council expert committee.3 Feldman describes the recent meta-analysis4 as selective and based on old, confounder-ridden studies. In support of her claims, she refers to two previous reports that reviewed some of the same studies, although without access to important background information. Feldman makes other serious errors—eg, by linking, without justification, a rise in population mean intelligent quotient (IQ) to the introduction of water fluoridation. Similarly, Gelinas and Allukian dispute the validity of previous studies on fluoride exposure and neurobehavioural deficits. We do not deny the importance of a doseresponse relation, which has been a unifying concept in toxicology since the time of Paracelsus. However, as we emphasised in our Review, emerging evidence on developmental neurotoxicity makes it clear that the timing of exposure is also of
great importance, especially during highly vulnerable windows of brain development. Due to the growing evidence on adverse effects, US authorities now recommend that fluoridation of community water should not exceed 0·7 mg/L.5 We agree with Wendroff’s perspective, but have been unable to identify epidemiological support for a claim of developmental neurotoxicity from exposure to mercury vapour. As elemental mercury might soon be added to the list of confirmed developmental neurotoxicants, we support the evidence-informed prevention of mercury exposures suggested by Wendroff. In writing our Review, we have tried to steer a middle course between advocates for particular public-health actions and spokespersons for the chemical industry. We believe that sufficient evidence is already available that industrial chemicals endanger human brain development and that unrestrained production and release of such chemicals are short-sighted, dangerous, unsustainable, and fundamentally immoral. We call for a thorough revision of chemical safety policies and for the establishment of a documentation centre on developmental neurotoxicity modelled after the International Agency for Research on Cancer. We declare no competing interests.
*Philippe Grandjean, Philip J Landrigan [email protected] Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark, and Department of Environmental Health, Harvard School of Public Health, Boston, MA 02215, USA (PG); and Department of Preventive Medicine, Mount Sinai School of Medicine, New York, NY; USA (PJL) 1
2
3
Grandjean P, Landrigan, P.J. Neurobehavioural impact of developmental toxicity. Lancet Neurol 2014; 13: 330–38. Cattani D, de Liz Oliveira Cavalli VL, Heinz Rieg CE, et al. Mechanisms underlying the neurotoxicity induced by glyphosatebased herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity. Toxicology 2014; 320: 34–45. National Research Council (NRC). Fluoride in drinking water: a scientific review of EPA’s standards. Washington, DC: The National Academies Press, 2006.
www.thelancet.com/neurology Vol 13 July 2014
Correspondence
4
5
Choi AL, Sun G, Zhang Y, Grandjean P. Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect 2012; 120: 1362–68. US Environmental Protection Agency. EPA and HHS Announce New Scientific Assessments and Actions on Fluoride. http://yosemite.epa. gov/opa/admpress.nsf/6427a6b7538955c585 257359003f0230/86964af577c37ab2852578 11005a8417!OpenDocument (accessed May 23, 2014).
Evidence or clinical implementation: which should come first? The Editorial1 in the June issue of The Lancet Neurology discusses the clinical potential of the Dutch ParkinsonNet—a multidisciplinary network of professionals that specialises in treatment of patients with Parkinson’s disease. The core of the network consists of allied health and other non-medical professionals who are trained to work according to clinical practice guidelines, who continuously increase their Parkinson’s-specific expertise by treating large caseloads, and who adopt a patient-centred, collaborative approach. The Editorial points to the value of ParkinsonNet for improvement of participatory medicine in clinical practice, but emphasises the need to gather further evidence before this multidisciplinary concept can be implemented in other health-care systems. This view is understandable in most scientific fields, but when multidisciplinary care is assessed, a chicken or egg discussion is at play: should we obtain evidence about multidisciplinary care and then implement it within professional networks; or should we start these networks first, even when little evidence is available, and exploit those networks to obtain the obligatory evidence that either supports or refutes the effectiveness of multidisciplinary care? We favour the latter strategy. It is not possible to obtain robust evidence
www.thelancet.com/neurology Vol 13 July 2014
for non-medical interventions such as physiotherapy or nursing when only inexperienced professionals are available who cannot deliver the intervention properly. Specialised networks such as ParkinsonNet offer the necessary infrastructure for clinical trials. Trained ParkinsonNet experts can deliver experimental interventions consistently, with little variation across practices, and in accordance with guideline recommendations or research protocols. We previously used the ParkinsonNet infrastructure to assess several allied health interventions. The first intervention was tested in a clustercontrolled trial which compared eight regions that had specialised ParkinsonNet physiotherapists with eight regions that had generically trained therapists only.1 ParkinsonNet therapists adhered better to guidelines and offered cheaper care than did generically trained therapists, but their clinical outcomes were comparable to those of usual care. The second intervention was tested in the ParkFit trial, that assessed whether personal coaches can promote a more active lifestyle in sedentary patients with Parkinson’s disease— coaches were specifically trained ParkinsonNet physiotherapists. 3 A third trial tested the effectiveness of occupational therapy, again using specialised ParkinsonNet therapists to deliver the intervention.4 Finally, we have done several studies within ParkinsonNet to assess the merits of integrated multidisciplinary care. We recently reported the results of a controlled, non-randomised trial that compared one region that had both a specialised Parkinson’s disease centre and a regional ParkinsonNet with two control regions that had neither.5 Our analyses showed minor benefits in favour of the integrated care model, but these disappeared after controlling for baseline differences. All these trials would have been impossible if the
network implementation had not preceded the studies. Importantly, the outcomes of these trials can be readily shared with all network participants, allowing for rapid implementation of new knowledge into everyday clinical practice. To disseminate fresh research findings, we increasingly use online communities where ParkinsonNet professionals meet to learn about the latest evidence.6 As such, ParkinsonNet creates an interesting infrastructure for health-care innovation, for high-quality research, and for quick dissemination of new evidence to committed professionals. BRB has received honoraria from sitting on the scientific advisory boards for GlaxoSmithKline, UCB, and Danone, and received research support and grants from The National Parkinson Foundation, the Netherlands Organisation for Scientific Research (NWO), the Michael J Fox Foundation, Prinses Beatrix Spierfonds, Stichting Parkinson Fonds, and Alkemade-Keuls Fonds. For the development of the Dutch ParkinsonNet, BB and MM received grants from ZonMw, Zorgverzekeraars Nederland, Parkinson Vereniging, Stichting Parkinson Nederland, Fonds Nuts Ohra, Prinses Beatrix Fonds, Michael J Fox Foundation, National Parkinson Foundation, Centraal Ziekenfonds (CZ), Stichting Volksgezondheidszorg (VGZ), and Achmea.
*Bastiaan R Bloem, Marten Munneke [email protected] Department of Neurology (935), Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands (BRB, MM) 1 2
3
4
5
6
Consumer choices in Parkison’s disease. Lancet Neurol 2014; 13: 525. Munneke M, Nijkrake MJ, Keus SH, et al. Efficacy of community-based physiotherapy networks for patients with Parkinson’s disease: a cluster-randomised trial. Lancet Neurol 2010; 9: 46–54. van Nimwegen M, Speelman AD, Overeem S, et al. Promotion of physical activity and fitness in sedentary patients with Parkinson’s disease: randomised controlled trial. BMJ 2013; 346: f576. Sturkenboom IH, Graff MJ, Hendriks JC, et al. Effectiveness of occupational therapy for patients with Parkinson’s disease: a randomised controlled trial. Lancet Neurol 2014; 13: 557–66. van der Marck MA, Munneke M, Mulleners W, et al. Integrated multidisciplinary care in Parkinson’s disease: a non-randomised, controlled trial (IMPACT). Lancet Neurol 2013; 12: 947–56. Bloem BR, Munneke M. Revolutionising management of chronic disease: the ParkinsonNet approach. BMJ 2014; 348: g1838.
649
