Neuro Development

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Page 1 of 5 Toxicological Sciences ToxSci Advance Access published March 25, 2008 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Modeling neurodevelopment outcomes and ethylmercury exposure from thimerosalcontaining vaccines. José G. Dórea,1 Ph.D., Rejane M. Correa,2 Ph.D., 1 Universidade de Brasília. Brasília, DF, Brasil. Fundação Universidade Federal de Rondônia. Por
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  All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology.  Modeling neurodevelopment outcomes and ethylmercury exposure from thimerosal- containing vaccines. José G. Dórea, 1 Ph.D., Rejane M. Correa, 2 Ph.D., 1 Universidade de Brasília. Brasília, DF, Brasil. 2 Fundação Universidade Federal de Rondônia. Porto Velho, RO;Correspondence:José G. DóreaC.P. 04322Faculty of Health Sciences, Universidade de Brasilia70919-970 Brasilia, DFBRAZIL dorea@rudah.com.br Key words: Thimerosal ; ethylmercury; vaccines; newborns; neurodevelopment. Running Head:  Modeling current ethymercury exposure. Page 1 of 5Toxicological Sciences 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960   ToxSci Advance Access published March 25, 2008  Dear Editor,The neurotoxic effects of ethylmercury (EtHg) accidentally consumed in Iraq weresufficient to withdraw ethylmercury-containing fungicides as seed dressing. Despite that,not only did thimerosal continue to be used in pharmaceutical preparations buttoxicological interest in EtHg derived substances also diminished considerably and wasnever addressed with regard to the small quantities used as a vaccine preservative.Thimerosal-containing vaccines (TCV) haveno record of overt clinical neurologicalconsequences due to EtHg and the plausibility of subtle neurotoxic effects in children hasbeenrecognizedonly recently by the USA and other industrialized countries. In this contextwe welcome the interesting work of Berman et al (2008); it is clear that this assiduous study(in immunologically susceptible mice) took into consideration doses and schedules of TCV-Hg concentrations that had beenused ininfants inthe USA. Theirmice modeldoesnot, however, cover the full extent of modifying factors associated with TCV-Hg exposurein the majority of immature and newborns around the world that still have to depend onTCV.According to Berman et al (2008) the USA vaccination scheduled exposed a total of 125µgHg distributed at two, four, and six months through TCV (hepatitis B and DTP). Thistype of vaccineis no longer used in industrialized countries butit isstill used all over theworld.We know that thimerosal concentrations vary among brands of vaccinesand alsothat immunization schedules vary depending on a country’s health policy; not only that, butnew outbreaks of disease introduce additional new vaccines (which may containthimerosal) during the first year of life. As an example,the public health services of Brazil,like other countries, stilluses several brands ofhepatitis-B vaccine (containing thimerosalas preservative) with concentrations ranging from 12.5 to 50µgHg per 0.5ml shot. Another Page 2 of 5Toxicological Sciences 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960  salient differencebetween countries that use TCV (like Brazil) andthe USA is thatin theformer country hepatitis B inoculation startswithin the first 12 to 24 hours after birth(Marques et al, 2007), and is administered to low-birth-weight =/> 2000g (SBIM, 2006)and premature babies who are also recommended a fourth shot as an additional booster(DI/DH/CVE, 2006). In such situations not only toxicokinetics (TK) but especiallytoxicodynamics (TD) of EtHgare entirely different between a one-day-old (with differentstages of immaturity and birth weight) and a sixty-day-old child (as modeled).The newborn presents several physiological degrees of immaturity in the excretorysystem (kidneys and bile formation) and target organ (central nervous system, CNS) thatare important modifiers of EtHg TK and TD. These features are inversely accentuated bygestational age and birth weight. Under such circumstances, unbound circulating EtHg in anewborn (and immature) may not be eliminatedas fast as in a two-month-old babyand thuswill be readier to cross the more vulnerable blood-brain barrier (BBB). The newborn BBBincreases in effectiveness with age; therefore, the free EtHg can more easily penetrate theimmature CNS (Dorea, 2007).As a consequence,the smaller the body size and bloodvolume the more alteredthe TD and TK of EtHg.Indeed, Stajich et al (2000) showed thatpreterm infants do not metabolize Hg efficiently.Collectively, studies show that largerbabies have significantly higher mean liver metallothionein than smaller babies (Dorea2007).Factors associated with protein binding capacity, excretion mechanisms, and enzymeactivities are immature in the neonate and modulate differences in adverse effects betweennewborns and infants exposed to neurotoxic substances. During the period of immaturity,not only plasma albumin but total protein concentrations decrease (Dorea, 2007).The bestexample in differences between neurotoxic effects is type of albumin and competition for Page 3 of 5Toxicological Sciences 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960  binding sites (due to increased circulatory concentrations of bilirubin). Albumin binding (tobilirubin) is less effective during the first post-natal days and,as a consequence, excess freebilirubin can cross the BBB at early stages of the post-natal CNS immaturity and causebrainstem abnormalities; albumin priming can be effective in attenuating effects caused byunbound bilirubin (Dorea, 2007).We do not dispute the conclusions drawn byBerman et al regarding Hg and theneurobiology of autism; however we think it is possible to take their findings one stepfurtherin regards to thimerosal neurotoxicity. We contend that these findings areappropriate for USA-like scenarios (as intended by the authors) but are not sufficient toaddress the current TCV schedules in the majority of newborns and infants around theworld. TCV are used worldwide in vaccination schedules that include more of thesevaccines at an earlier age.Unfortunately, the differences that set newborns (especially low-birth-weights and prematures)apart from two-month-old infants have not yet been modeledin experimental studies and remain neglected in TK and TD knowledge of TCV-EtHgexposure.We hope that studies like Berman et al (2008) can inspire conventionaltoxicology to address uncertainties regarding current serial EtHg exposure in newborns andinfants that have to take TCV. Page 4 of 5Toxicological Sciences 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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