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Integrating Experimental Neurotoxicity Studies of Low-dose Thimerosal Relevant to Vaccines

Integrating Experimental Neurotoxicity Studies of Low-dose Thimerosal Relevant to Vaccines

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Published by Starxteel
Abstract
There is a need to interpret neurotoxic studies to help deal with uncertainties surrounding pregnant mothers, newborns and young children who must receive repeated doses of Thimerosal-containing vaccines (TCVs). This review integrates information derived from emerging experimental studies (in vitro and in vivo) of low-dose Thimerosal (sodium ethyl mercury thiosalicylate). Major databases (PubMed and Web-of-science) were searched for in vitro and in vivo experimental studies that addressed the effects of low-dose Thimerosal (or ethylmercury) on neural tissues and animal behaviour. Information extracted from studies indicates that: (a) activity of low doses of Thimerosal against isolated human and animal brain cells was found in all studies and is consistent with Hg neurotoxicity; (b) the neurotoxic effect of ethylmercury has not been studied with co-occurring adjuvant-Al in TCVs; (c) animal studies have shown that exposure to Thimerosal-Hg can lead to accumulation of inorganic Hg in brain, and that (d) doses relevant to TCV exposure possess the potential to affect human neuro-development. Thimerosal at concentrations relevant for infants’ exposure (in vaccines) is toxic to cultured human-brain cells and to laboratory animals. The persisting use of TCV (in developing countries) is counterintuitive to global efforts to lower Hg exposure and to ban Hg in medical products; its continued use in TCV requires evaluation of a sufficiently nontoxic level of ethylmercury compatible with repeated exposure (co-occurring with adjuvant-Al) during early life.
Abstract
There is a need to interpret neurotoxic studies to help deal with uncertainties surrounding pregnant mothers, newborns and young children who must receive repeated doses of Thimerosal-containing vaccines (TCVs). This review integrates information derived from emerging experimental studies (in vitro and in vivo) of low-dose Thimerosal (sodium ethyl mercury thiosalicylate). Major databases (PubMed and Web-of-science) were searched for in vitro and in vivo experimental studies that addressed the effects of low-dose Thimerosal (or ethylmercury) on neural tissues and animal behaviour. Information extracted from studies indicates that: (a) activity of low doses of Thimerosal against isolated human and animal brain cells was found in all studies and is consistent with Hg neurotoxicity; (b) the neurotoxic effect of ethylmercury has not been studied with co-occurring adjuvant-Al in TCVs; (c) animal studies have shown that exposure to Thimerosal-Hg can lead to accumulation of inorganic Hg in brain, and that (d) doses relevant to TCV exposure possess the potential to affect human neuro-development. Thimerosal at concentrations relevant for infants’ exposure (in vaccines) is toxic to cultured human-brain cells and to laboratory animals. The persisting use of TCV (in developing countries) is counterintuitive to global efforts to lower Hg exposure and to ban Hg in medical products; its continued use in TCV requires evaluation of a sufficiently nontoxic level of ethylmercury compatible with repeated exposure (co-occurring with adjuvant-Al) during early life.

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02/04/2013

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OVERVIEW
Integrating Experimental (In Vitro and In Vivo) NeurotoxicityStudies of Low-dose Thimerosal Relevant to Vaccines
Jose´G. Do´rea
Accepted: 12 February 2011
Ó
Springer Science+Business Media, LLC 2011
Abstract
There is a need to interpret neurotoxic studiesto help deal with uncertainties surrounding pregnantmothers, newborns and young children who must receiverepeated doses of Thimerosal-containing vaccines (TCVs).This review integrates information derived from emergingexperimental studies (in vitro and in vivo) of low-doseThimerosal (sodium ethyl mercury thiosalicylate). Majordatabases (PubMed and Web-of-science) were searched forin vitro and in vivo experimental studies that addressed theeffects of low-dose Thimerosal (or ethylmercury) on neuraltissues and animal behaviour. Information extracted fromstudies indicates that: (a) activity of low doses of Thi-merosal against isolated human and animal brain cells wasfound in all studies and is consistent with Hg neurotoxicity;(b) the neurotoxic effect of ethylmercury has not beenstudied with co-occurring adjuvant-Al in TCVs; (c) animalstudies have shown that exposure to Thimerosal-Hg canlead to accumulation of inorganic Hg in brain, and that(d) doses relevant to TCV exposure possess the potential toaffect human neuro-development. Thimerosal at concen-trations relevant for infants’ exposure (in vaccines) is toxicto cultured human-brain cells and to laboratory animals.The persisting use of TCV (in developing countries) iscounterintuitive to global efforts to lower Hg exposure andto ban Hg in medical products; its continued use inTCV requires evaluation of a sufficiently nontoxic levelof ethylmercury compatible with repeated exposure(co-occurring with adjuvant-Al) during early life.
Keywords
Children
Á
Infants
Á
Neurodevelopment
Á
Pregnancy
Á
Ethylmercury
Á
Thimerosal
Introduction
The prevalence of emerging neuro-developmental disabil-ities has been directly linked to environmental neurotoxicsubstances which are estimated to affect 3% of children[1]; environmental mercury exposure, mainly methylmer-cury from seafood [1] and elemental mercury from coalcombustion (used in electrical utilities) as well as muni-cipal and medical waste incinerators [2], is at the center of concerns. However, a considerable part of these disabilities(25%) may arise as a result of interaction with individualgenetic susceptibilities [1]. Indeed it is known that Hgneurotoxicity involves long latencies and atypical respon-ses between low and high doses [3]; additionally, it hasnow been shown that exposure to different forms of mer-cury (such as methylmercury and Hg vapor) can act syn-ergistically in increasing neurotoxic risks [3].Organic and inorganic forms of mercury have a longhistory of use in medicine and pediatrics. Until the 1950smercury preparations were part of the therapeutic resourcesto deal with common childhood ailments [4]. Because of itsrole in pink disease and also with the advent of morespecific therapeutic drugs, mercury formulations have beenwithdrawn from children’s medication [4]. Nevertheless,Thimerosal (sodium ethyl mercury thiosalicylate) hasremained in wide use as a preservative in pharmaceuticalproducts. Thimerosal in topical formulations has beeneliminated in many parts of the world but its use in vac-cines for pregnant women, newborns and young childrencontinues in developing countries [5]. Although breast-fedinfants can be exposed to elemental Hg from maternal
J. G. Do´rea (
&
)Faculty of Health Sciences, Universidade de Brası´lia,C.P. 04322, 70919-970 Brası´lia, DF, Brazile-mail: dorea@rudah.com.br
 123
Neurochem ResDOI 10.1007/s11064-011-0427-0
 
dental amalgam [6], outside the most developed countries,ethylmercury (EtHg), the metabolite of Thimerosal,remains the first exposure a vaccinated infant has to apotentially neurotoxic substance.Thimerosal(whichis49%EtHg)isusedasapreservative(at 0.01% of the formulation) in multidose vials of somevaccines. Thimerosal has been in use since the 1930s and itonly became a toxicological issue in the early 2000s whenpublichealthprofessionalsintheUSAraisedconcernsaboutpossible untoward effects caused by EtHg on newborns andinfants. Thimerosal is known as a contact allergen, andcaution has been urged regarding significant side effects intherapeuticagents[7]andinvaccines[8]withspecificissues related to infant-CNS (central nervous system); however, itseffects have been focused only relatively recently [9].Indeed,theseissuesremainoutside thescope ofsurveillanceofpost-licenseThimerosal-containingvaccine(TCV)safety[10]. Post-vaccine adverse-effects that receive attention arerestricted to extreme cases of reactogenicity (from compo-nents other than preservatives and adjuvants). Althoughthere are neurologic adverse reactions related to vaccines,they do not capture long latencies compatible with low-doseHg toxicity. Rare adverse neurologic reactions followingvaccination include clinical syndromes such as encepha-lopathy, Guillain–Barre syndrome, meningo-encephalitis,poly-neuropathy, peripheral neuritis, per se or in combina-tion [11]; these clinical syndromes can occur in associationwith vaccines (rabies, diphtheria-tetanus-polio, smallpox,measles,mumps,rubella,Japanese Bencephalitis, pertussis,hepatitis B, and influenza) that may or may not containThimerosal. Furthermore, these reactions occur hours orwithin few weeks after vaccination [11] and are not com-patiblewithlow-doseexposuretomercury.However,recentincrease in neuro-developmental disorders has been thor-oughly discussed in relation to vaccines, addressing bothimmunologic and neurotoxic issues related to Thimerosal[12].Environmental safety managers and public health pro-fessionals have attributed neurologic risks to Hg contami-nation and have successfully educated the public about theundesirable effects of exposure to it through fish con-sumption and dental amalgam; these concerns are nowextended to populations living in developing countrieswhere TCVs are largely used [13]. Such efforts have led toa general awareness of mercury in pharmaceuticals and, asa result of withdrawing Thimerosal from medicines, adeep-rooted concern has emerged regarding the presence of Hg in vaccines still in use for pregnant mothers, newborns,and infants. The WHO convened a group of experts thatexamined the complexities surrounding production and useof TCV [14]. The Organization’s decision to uphold TCV-Hg safety was based on expert opinions when scientificinformation on low-dose effects of Thimerosal was limited.Vaccine-Thimerosal exposure is an important pre- andpost-natal neurotoxic stressor. In this regard, in vitro testsare useful to unravel mechanisms of specific effects causedby toxic substances while animal controlled experimentscan extract information on exposure, dose, and relatedtoxic outcomes. We still do not have an integrated over-view of current knowledge that could serve as a tool toguide the decisions of pediatric and health professionalsand help them to debate effectively the uncertainties pos-ited by conventional toxicology on the safety of low-doseexposure to TCV.Parental attitude towards perception of vaccine safetyhas changed over the last decade in some of the mostdeveloped countries. Freed et al. [15] have just reportedthat a ‘disturbingly high proportion of parents (25%)’believe vaccines can cause neurodevelopment problems,adding that current public health campaigns have notbeen effective. Parental-guidance reference books adviseexpecting mothers to avoid Hg exposure from sources thatinclude TCV [16]. Meanwhile, there are demands forregulatory agencies to control residual Thimerosal incountries that are no longer using it in infant’s vaccines[17]. There is a clear need to address uncertainties relatedto vaccine preservatives, and it centers on Thimerosal [18].Therefore, this research focuses on the emerging experi-mental studies (in vitro and in vivo) that have addressed theeffects of small doses of Thimerosal on neural cells andanimal tissues and motor and behavioural functions. Thisreview aims to integrate experimental (in vitro and in vivo)studies on the potential impact of Thimerosal in vaccinesstill liberally used in pregnant women and infants. Table1shows some of the neurotoxic mechanisms at cellular level,whereas Table2summarizes toxicokinetic and toxcody-namic information relevant to TCV-Hg.
In Vitro Tests
Although Thimerosal is the preservative of choice formultidose vaccine vials, it may not be the most effective.Thimerosal may fail to prevent short-term bacterial con-tamination [19] and it can also destabilize antigens [20,21]. Geier et al. [22] tested several compounds routinely used inthe US; they reported that the concentration of Thimerosalnecessary to induce bacterial cell-death was higher than thatactually found in the US products. Furthermore, the phenol-preserved vaccine showed less proteolytic activity than theThimerosal-preserved one [23]. Such relative limitationsare now coupled with experimental studies consistentlyshowing neural-cell toxicity caused by Thimerosal at con-centrations relevant to vaccines. Compared to other vaccinepreservatives, Thimerosal showed a relatively higher tox-icity (phenol
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2-phenoxyethanol
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benzethonium chloride
Neurochem Res
 123
 
      T    a      b      l    e      1
    S   u   m   m   a   r   y   o    f   t   o   x    i   c    i   t   y   s   t   u    d    i   e   s   o    f    l   o   w  -    d   o   s   e    T    h    i   m   e   r   o   s   a    l    (   o   r   e   t    h   y    l   m   e   r   c   u   r   y    )   a   n    d   a    l   u   m    i   n   u   m    i   n    h   u   m   a   n   a   n    d   a   n    i   m   a    l   c   u    l   t   u   r   e    d  -   n   e   u   r   a    l  -   c   e    l    l   s    R   e    f   e   r   e   n   c   e    S   p   e   c    i   e   s    C   e    l    l   t   y   p   e    C   o   m   p   o   u   n    d    D   o   s   e    M   e   a   s   u   r   e    d   o   u   t   c   o   m   e   s    G   e    i   e   r   e   t   a    l .    [    2    2    ]    H   u   m   a   n    N   e   u   r   o    b    l   a   s   t   o   m   a    (    S    H  -    S    Y  -    5    Y    )    T    h    i   m   e   r   o   s   a    l   c   o   m   p   a   r   e    d   t   o   o   t    h   e   r   v   a   c   c    i   n   e   p   r   e   s   e   r   v   a   t    i   v   e   s    1
     l
    M  –    1    0
     l
    M    R   e    l   a   t    i   v   e   t   o   x    i   c    i   t   y   :   p    h   e   n   o    l
     \
    2  -   p    h   e   n   o   x   y   e   t    h   a   n   o    l
     \
    b   e   n   z   e   t    h   o   n    i   u   m   c    h    l   o   r    i    d   e
     \
    T    h    i   m   e   r   o   s   a    l    G   e    i   e   r   e   t   a    l .    [    3    3    ]    H   u   m   a   n    N   e   u   r   o    b    l   a   s   t   o   m   a    (    S    H  -    S    Y  -    5    Y    ) ,   a   s   t   r   o   c   y   t   o   m   a    (    1    3    2    1    N    1    )   ;    f   e   t   a    l    (   n   o   n   t   r   a   n   s    f   o   r   m   e    d    )   m   o    d   e    l   s   y   s   t   e   m   s    T    h    i   m   e   r   o   s   a    l    1    0   n    M  –    1    0
     l
    M    T    i   m   e  -    d   e   p   e   n    d   e   n   t   m    i   t   o   c    h   o   n    d   r    i   a    l    d   a   m   a   g   e   ;   r   e    d   u   c   e    d   o   x    i    d   a   t    i   v   e  –   r   e    d   u   c   t    i   o   n   a   c   t    i   v    i   t   y   ;   c   e    l    l   u    l   a   r    d   e   g   e   n   e   r   a   t    i   o   n   ;   a   n    d   c   e    l    l    d   e   a   t    h    J   a   m   e   s   e   t   a    l .    [    3    6    ]    H   u   m   a   n    L   y   m   p    h   o    b    l   a   s   t   o    i    d    d   e   r    i   v   e    d    f   r   o   m   c    h    i    l    d   r   e   n   w    i   t    h   a   u   t    i   s   m    T    h    i   m   e   r   o   s   a    l    0 .    1    5    6  –    2 .    5
     l
    M    D   e   c   r   e   a   s   e    d   t    h   e   r   e    d   u   c   e    d   g    l   u   t   a   t    h    i   o   n   e    /   o   x    i    d    i   z   e    d    d    i   s   u    l    fi    d   e   g    l   u   t   a   t    h    i   o   n   e   r   a   t    i   o   a   n    d    i   n   c   r   e   a   s   e    d    f   r   e   e   r   a    d    i   c   a    l   g   e   n   e   r   a   t    i   o   n    i   n   a   u   t    i   s   m   c   o   m   p   a   r   e    d   t   o   c   o   n   t   r   o    l   c   e    l    l   s    H   e   r    d   m   a   n   e   t   a    l .    [    3    2    ]    H   u   m   a   n    N   e   u   r   o    b    l   a   s   t   o   m   a    S    K  -    N  -    S    H    l    i   n   e    T    h    i   m   e   r   o   s   a    l ,   c   o   m   p   a   r   e    d   t   o   t    h    i   o   s   a    l    i   c   y    l   a   t   e    0  –    2 .    5
     l
    M    N   e   u   r   o   t   o   x    i   c    i   t   y   o   c   c   u   r   s   t    h   r   o   u   g    h   t    h   e    J    N    K  -   s    i   g   n   a    l    i   n   g   p   a   t    h   w   a   y ,    i   n    d   e   p   e   n    d   e   n   t   o    f   c    J   u   n   a   c   t    i   v   a   t    i   o   n ,    l   e   a    d    i   n   g   t   o   a   p   o   p   t   o   t    i   c   c   e    l    l    d   e   a   t    h    P   a   r   r   a   n   e   t   a    l .    [    3    4    ]    H   u   m   a   n    N   e   u   r   o    b    l   a   s   t   o   m   a    (    S    H  -    S    Y    5    Y    )    T    h    i   m   e   r   o   s   a    l    1   n    M  –    1    0
     l
    M    A    l   t   e   r   n   e   r   v   e   g   r   o   w   t    h    f   a   c   t   o   r   s    i   g   n   a    l   t   r   a   n   s    d   u   c   t    i   o   n   ;   c   a   u   s   e   s   c   e    l    l    d   e   a   t    h   a   n    d   e    l   e   v   a   t   e    d    l   e   v   e    l   s   o    f    f   r   a   g   m   e   n   t   e    d    D    N    A    Y   e    l   e   t   a    l .    [    3    0    ]    H   u   m   a   n    N   e   u   r   o    b    l   a   s   t   o   m   a ,    C    R    L  -    2    2    6    8    T    h    i   m   e   r   o   s   a    l    0 .    0    2    5  –    5 .    0
     l
    M    N   e   u   r   o   n   a    l   c   e    l    l    d   e   a   t    h   t    h   r   o   u   g    h   t    h   e   m    i   t   o   c    h   o   n    d   r    i   a    l   p   a   t    h   w   a   y    (    d   e   p   o    l   a   r    i   z   a   t    i   o   n   o    f   m    i   t   o   c    h   o   n    d   r    i   a ,   g   e   n   e   r   a   t    i   o   n   o    f   r   e   a   c   t    i   v   e   o   x   y   g   e   n   s   p   e   c    i   e   s ,   r   e    l   e   a   s   e   o    f   c   y   t   o   c    h   r   o   m   e   c   a   n    d   a   p   o   p   t   o   s    i   s  -    i   n    d   u   c    i   n   g    f   a   c   t   o   r    )    J   a   m   e   s   e   t   a    l .    [    2    7    ]    H   u   m   a   n    N   e   u   r   o    b    l   a   s   t   o   m   a    (    S    H  -    S    Y    5    Y    C    R    L    2    2    6    6    )   a   n    d   g    l    i   o    b    l   a   s   t   o   m   a    (    C    R    L    2    0    2    0    )    T    h    i   m   e   r   o   s   a    l    1    5
     l
    M
     \
    5    0    %    d   e   c   r   e   a   s   e    i   n    i   n   t   r   a   c   e    l    l   u    l   a   r   g    l   u   t   a   t    h    i   o   n   e    l   e   v   e    l   s    i   n   t    h   e   g    l    i   o    b    l   a   s   t   o   m   a   c   e    l    l   s    b   u   t   m   o   r   e   t    h   a   n   e    i   g    h   t    f   o    l    d  -    d   e   c   r   e   a   s   e    i   n   t    h   e   n   e   u   r   o    b    l   a   s   t   o   m   a   c   e    l    l   s    H   u   m   p    h   r   e   y   e   t   a    l .    [    3    1    ]    H   u   m   a   n    N   e   u   r   o    b    l   a   s   t   o   m   a ,    S    K  -    N  -    S    H    l    i   n   e    T    h    i   m   e   r   o   s   a    l    5
     l
    M    D   e    l   e   t   e   r    i   o   u   s   e    f    f   e   c   t   s   o   n   t    h   e   c   y   t   o   a   r   c    h    i   t   e   c   t   u   r   e    l   e   a    d    i   n   g   t   o   m    i   t   o   c    h   o   n    d   r    i   a    l  -   m   e    d    i   a   t   e    d   a   p   o   p   t   o   s    i   s   a   n    d   o   n   c   o   s    i   s    /   n   e   c   r   o   s    i   s    W   a    l   y   e   t   a    l .    [    3    5    ]    H   u   m   a   n    S    H  -    S    Y    5    Y   n   e   u   r   o    b    l   a   s   t   o   m   a    T    h    i   m   e   r   o   s   a    l    1   n    M    I   n    h    i    b    i   t    i   o   n   o    f    b   o   t    h    I    G    F  -    1  -   a   n    d    d   o   p   a   m    i   n   e  -   s   t    i   m   u    l   a   t   e    d   m   e   t    h   y    l   a   t    i   o   n   w    i   t    h   a   n    I    C    5    0   o    f    1   n    M   a   n    d   e    l    i   m    i   n   a   t   e    d   m   e   t    h   y    l   a   t    i   n   g   a   c   t    i   v    i   t   y    T   o    i   m   e    l   a   a   n    d    T   a    h   t    i    [    4    2    ]    H   u   m   a   n    S    H  -    S    Y    5    Y   n   e   u   r   o    b    l   a   s   t   o   m   a ,    U    3    7    3    M    G   g    l    i   o    b    l   a   s   t   o   m   a    A    l   u   m    i   n   u   m    0 .    0    1  –    1 ,    0    0    0
     l
    M    A    l   w   a   s   e    f    f   e   c   t    i   v   e    i   n    i   n    d   u   c    i   n   g   a   p   o   p   t   o   s    i   s   o    f   g    l    i   o    b    l   a   s   t   o   m   a    B   a   s    k    i   n   e   t   a    l .    [    2    9    ]    H   u   m   a   n    C   o   r   t    i   c   a    l   n   e   u   r   o   n   s    T    h    i   m   e   r   o   s   a    l    1  –    2    5    0
     l
    M    C    h   a   n   g   e   s    i   n   c   e    l    l   m   e   m    b   r   a   n   e   p   e   r   m   e   a    b    i    l    i   t   y   ;    i   n    d   u   c   t    i   o   n   o    f    D    N    A    b   r   e   a    k   s   ;   a   p   o   p   t   o   s    i   s    L   a   w   t   o   n   e   t   a    l .    [    3    9    ]    M   o   u   s   e   a   n    d   r   a   t    R   e   s   p   e   c   t    i   v   e    l   y    N    2   a   n   e   u   r   o    b    l   a   s   t   o   m   a   a   n    d    C    6   g    l    i   o   m   a   c   e    l    l   s    T    h    i   m   e   r   o   s   a    l    1
     l
    M    I   n    h    i    b    i   t    i   o   n   o    f   n   e   u   r    i   t   e   p   r   o   c   e   s   s   o   u   t   g   r   o   w   t    h    i   n    d    i    f    f   e   r   e   n   t    i   a   t    i   n   g    N    2   a   a   n    d    C    6   c   e    l    l   s
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