Document bwLXygZvO680X35184oBzKbZ
3j
^INTERNATIONAL LEAD ZINO RESEARCH OROANIZATION, INC.
SEE MAO'ION AVfNUE, NEW
N T. 0O*E
TM*MON| V*-E4>0 1AM* 0009 E*E*
OAV|
MV4.IEO NEW W
February 6, 19$7
Tot All HecA>rs of th* Lead torlraaoeatel Baoith Cotnltta* 1
Bat Ih-llb Proposal froo FPt*r P. Sew 11 >r
Attached for your consideration 1* a ccnplet* copy of the propoeal ** received frcn Foater D. Soell. Thla 1* th* flret prcpoeal that v* hart received that cone* cloee to what ve bar* la alod for thle f tixly. Sloe* thla la tb* fourth or fifth proposal to arrive la our office, I nu*t coo* elute that la general Aeertcan ta*icolo*tata ar* not vary well laforned about conditioned refla* typ* lnvetl**tloo*. Severer, X bop* to bav* other* for your consideration la th* near future.
If .you bat* any au***atlooa or cooaeat* about thla project aod thla propoaal, X ahall b very pleased to r*c*lv* thca at aoy tlaa. Kindly keep thla document la your file* for future reference, a* >m vlll b* considering awarding a contract la th* o#ar future, X bop*.
a- Very truly your*.
I
i COFiaw enclosure
Coo 0. Fowler Project Manager
a
MNTIRNATIONAL LIADZINO RBIIARCH ORQANIZATION, INO.
tva U40*0H AvINUl M OA< H . MW? t u mmo m r Ma u ia o o o 0*i AOOAiaa HViitAO ***w TO4
it1
-
- '4
4
.
1
IH-llk beurophyeloloKlcal Effect* frcn bead Exporur*
roam d . axnx lac. Cbaaltt* En*la*era Biologist*
A Subsidiary of Bo o k Alloa Applied Research Xae.
Biological Bcltncs Laboratory 150} Jarrett Else* Bronx, B.T. lC*6l Art* Cod* 212 828-3^03 January 23, 1967
Mr. Donald fcwlar Project Manager lotamat local Lead-line Research Orgaaliatloa
292 Madlaon Avasu* r* York, Rv York
> -
Daar Mr. Towlsri
ttiaak you very such for taking the tla* to vlalt our faetlltla* on January 12tb to discus* your need for the etudlee to 4aaon*trat* tb* safety of lead Ingestion at pr*<nt level*. W* bar*, aa you know, reviewed available eiperl&ental data vt.lc.'i baa caused cca concern aaoc( govermental official*. A protocol ha* been prepared by the** laboratories to attaapt to resolve tb*** question*. Tbl* la presented la tbl* letter la the following 7 **ctlonai
Objective
. Our Understanding of tb*
ProfelM
. Our Approach to tha Problea
. The Progran
. Organisation of tb Sort
. Our Qualification*
. Zetlaated Tla* and Co*t
ObJICTm
^
D**ptt* recent reviews 1 shoving that there *batld be no object too
to current level* of lead Intake la the United State*, dentbt cent In*;** 10 eiStt a* to the p.>*iM* effect* of thl lnee*tlon, A *t'j4y 1* needed to licit any *hd all effect* r*ear>J)e of their aln-or nature, folltvlrg chronic ingestion of the accepted aaxUua tolerated dose of lead.
t
V'
Haley, T. J., Arch, Environ. Health 1. 781 (l`>66)
*
k'
is 465.01
Mr. Donald fowler January 23, 1967 Page Two
OUR UKPgRStMfPDC 07 THE PROBLEM
A review of the literature cm 'Mr Pollution and Related Disease*"
bow* that the Russians have adopted a ouch lower maximum "isfe-level"
for laad than la considered applicable la the United State*. Changes la
behavior, learning, and/or memory have been reported in the USSR
following relatively low level* of Inorganic lead ingestion *,3. Recently,
In reporting functional shifts in higher nervous activity. It baa been
suggested that the people of the United States are being subjected to
chronic lead Insult frct industrial sources^. However, In direct con
tradiction, Dr. Those* 3. Haley cf Los Angeles, after reviewing the
subject, caae to the conclusion that 'the supposed chronic lead intox
ication frae environmental contamination is a myth, not a fact'. These
conflicting reports have raised doubt In the minds of public health officials
as to the safety of these levels of lead Ingestion.
_> ,
It has thus became necessary to carry out studies to demonstrate the safety of continued Ingestion of lead at present levels. Since aany studies have shown that no overt, cllnlcally-evldcnt shifts In biochemical, metabolic or physiologic functions occur, the new experiments Bust be directed toward evaluation of alniaal shifts in activity or performance* the so-called tub-clinical effects.
CUR AmCACM TO 7g PRC? LEM
' Cor program is Intended to define performance decrements following
lngestloo of graded levels of lead Intakes. The doses selected should be
V
equal to or part of the usual buxan Intake to be valid aa Indicators of
-
effects of present exposure levels. So significant biochemical or met
abolic studies are contemplated nor will there be any overt effort intended
to show alterations In tissue or cellular architecture. Rather, alterations
la behavior, mental performance and muscular work output are sought.
The experimental design taa teen selected so that the probability of
finding as little as a ID per cent shift la total performance will be high,
l.e., greater than 99 per cent.
.2 Ahalaubends, Y.t., Olgtere* 1 lanltsrly* 1, 791 (199?)
3- Olavnoy. T., Oeoflilcheskoy Cbservatorll leeft1 A.l. Voyeykov,
(WJ)
b. Patterson, C.C., Artb, JCnvtron. Health ^1, JAW (1969)
s? 5If ;?!P-_ . .
1 im-em1'!* ij 'ii i1
mmV
r
lb* t**k aaalgnad to tat anl*al* vill Include
si
. Doclaion Baking
-S . learning capacity
. Yltual recognition
;">S
. >tuculajr work output
. Muacular coordination
< Tbo alrgl* parameter to to followed 1* tin* for ccapletloo of five run* .
lhra|S a b o x *, tbua reflecting ruoaatlon of all of that* peyeboeotor,
function*. A* a alaplo, dlroct evaluation of total capability. It lo ;
Lntondod to abov any rate1Inical offoct of load.
'
Although no effort la to bo aod* to dalinaato tbo alt* of activity. If any, of tbo l*ad aalta, thia 6-oonth Ion* atudy aay parol t *c m* valuation of tbo *rfocta of lead on other nornal phytiolcglcal developMet a aucb aa growth, food intake, fecea fomatloa, tie. 8cao prollainary Indication about carcinogenic offact* of chronic feeding of accepted l*rla of Inorganic lead aalta nay alao be fcrtbccnlng.
'j Tbo hlghoat level to bo adalnlatered to tbo teat anlaala la to
; bo the equivalent of tbo daily intake of 0.33 ** lead per buaaa).
Aaaualng that the average nan voigba approximately 100 pound*, thla la an ingeation of O.OT5 *t por kg per day, the hlgheal dooo to bo uaed la theao otudioa. tvo lower dooea, 0.0> and 0.0075 g P*r kg per day, are Included ao that tbo throe do*** are in geometric prcgroaaloa uaLrg tbo aquaro root of 10 aa tbo factor. A doa* reapena* curve can then bo plotted logarithmically permitting ccaparlaon aacng treated group-* and between each group and the fourth group, the control*, receiving no doao.
:*
5. teboo, A.A., Arch, Environ. Health, 8, 232 (1fjO>)
0
5TW'i^5P' i*+,l!. ! JJWUlJfMi
Hr. Donald Fowler
January 23, 1967 Paga four
Tba test Beterlal la to be administered In the diet alaca orer 90 par cant of tba dally laad lnta*a in nan occura par oa. The concentration In the food will ta aalactad to five the defired level of laad Ingestion. Va feel that you ahould suggest tba laad ealt to ba uaad fron your know* ledge of the availability and utility of tba varloua ccopounda.
The weight, food conaunptlco and efficiency of food utilisation win ba followed cloaaly a Inca theaa have been reported to ba tba noat uaaful parameters 1a showing toxicity.
Performance la to ba followed In 6 anInals par croup par wek ualnc a water naze (Figure 1). The total e lapeed tine for five rune frca Introduction (A) to arrival at food cup (F) will ba delerained for each rat. Kiruler activity will affect coa^letloo of tba water courea (B). Decleloc asking occura at two point* (Cj and Cj) aid Macula?
coordination will ba reflected la alapaed time for movement up tba' Inclined plane (D). At Cj the rat ta preaented with a vlrual problan aeelnc the enpty food cup (E) and the deal red cup (F), which haa a fuel liar narking. At all feeding periods each rat la to ba preaentad with two cupa, one full and bearing specific aarklrgs and one anpty and unaarked. If there la no difference In learning potential between treated and control rata than we anticipate that all rat frcupa will make tba equivalent ouster of correct decisions at point Cj.
.
Ualnc 36 rata par croup la * 2^-wrek feeding study we will hare put all the rata through the test period In the Initial 6-week period. These will then be re.ndo.lied and used again during the second 6-week
(7 through 12). the third 6-week (13 through 16} and tba final (19 through 2t) week periods. During these subsequent trials, ncaory and data retentlca will also ba factors.
At that tlae the data will ba reviewed and tba findings presented
to tba International Lead-Zinc Keaearch Crganliattcm for decisions aa
to further studlee. Our progran does not Include provisions for sac
rifice, or for blochealcal or histological studies, el
yj blood and
urine seaplea art to ba collected periodically.
6. Kahoa, A.A., ). toy lost. Pub. Health Itj*.,
6l (1961)
o
rr:. .
v.o.d
jae*1 *
JgMPeww1
Tfcia prograa 1* directed twud elucidation of any cha&gaa ia perforaance baaed oa peycboootor activity. The total tuk involving, u it doee, exertion, coordination and peychlc activity abculd *bov any rubellnlcal rfftetr that aria*.
THZ PSOGRAM
A total of lUb aala, vaanling rata will ba ueed ia thla etudy,
divided into four froupa of tach aa follovat `i
croup i -
ccemcta
receiving * ground baaal (ccaoarclal)
ration i
' % % i
Croup IX
U
receiving a ground baaal ratloQ coo tainlng ruffle lent lead aalta to 1
in
yield a dally intake of lead of 0.0075 * per kg.
ri*
' i-
Croup III
KID
receiving * ground baaal ratloo cco tainlng ruffle lent lead aalta to
yield a dally intake of 0.035 g
par kg.
'-`5
Croup It -
HICK
receiving a ground baaal ratios cco. tainlng eufficlent lead aalta to
yield a dally Intake of 0.075 g
par kg.
..1
.4
Food will be available coe hour par day, 6 daya par veek. The food nip* will be plainly ranked. At the tine of pre rental ion of the food a eecond,
espty, umarked, cup vl 11 U placed la the cage. Aaple auppliaa of freab
tap water vill be available at all tinea.
The rale vlU b* bouaad individually la raleed-floor, vire-neah cage*. Ctaervatioae vlil be aa-le dally for rurvlval, behavior, appearance of the arcreta, and general phytical ceeviillcvt. Food intake and bedgr welghta for 10 rata per group will be recc-rde-i weekly and efficiency w foed util* italic* (g gained per ICO g food eaten) calculated after 12 veeka.
,
0
" " Mv - * ` Ska- ~ ,
was?* - . :
y f e.
Mr. Donald fowler January 23, 1967 !> Six
On the fifth day of the study and weekly thereafter (after a M3-hour feet), 6 rata of each group will ha Introduced to the amt* and total tlM for 5 trial* for each rat determined. Comparison* will be made among group* to determine performance differences. Each rat will thus be tested U times, once during each of the four 6-week periods of the Study. In addition to the objective criterion of elapsed time, subjective eval uation of rat performance will also be made.
The data reported will reflect effecte of the various doses ca
growth and mental and muscular performance. At th* end of each 6-week
period these eacplee will be collected from 10 rat* per grcwp other
than thoee used for food eoesumytloa and weight measurements, and
these will be stored at ~20^C should analysis becoes desirable at seme
future time. The snlsals will be sacrificed only es directed by the.
International Lead-Zinc Research Organisation.
., ,
cfCATOArioa or rat w o h c
Th* project will be carried cut under ay supervision. A short
resume rjzzmrltlng my capabilities end backgrcund and a bibliography
describing ay past effort* have been Included for ycur review. The
epee If ic
vert will be carried cut by Rr. Juan Dorado, Senior
Technician with uststaac* fora Dr. Aielfo Hemandes, Research
Veterinarian. Specific assistance la the psychological studies will
be given by Nr. Harold Uallach ho has been engaged In behavioral
research for 8 year*. Animals handlers will be assigned as needed.
The data will be reviewed oathematically by Dr. Theodor* Homer, Senior Statistician of Soot, Allen Applied Research, lac.
As Senior Investigator, I will tutnit s letter report to th* Organ it st Ion approximately once per month during th* course of th# etudiee. A (Quarterly report reflecting th# findings during the first and ssc-.cvd &-v**x period* will be Israel after the first 12 week* of th# Study a/>l a formal final report will be issued after 2L week# during which ttrm the anlaals will still be alive. TM* 1* expected to permit th# Organisation to decile the future of these test anlaele.tgr
/
HCyu.
' 53?-'; ^ Vi;; ]
n>
A
I-
f. -
'-j 5
L
-3
&
!
f?
s
dm QUAUTICATIOBa
lb* specific personnel to be assigned to the project ere described above.
The combined experience of our personnel In toxicological and behavioral studies will be brought to bear In tbe solution of this problem.
Studies Involving administration of drugs, foods, cosaetlcs, and chemicals b/ oral, ocular, topical, parenteral, and inhalation routes have been carried out In this facility vithln the past year. Clinical and blochealcal laboratories are located co the premise*, end a complete histological service 1* maintained. In addition to Investigations per formed with animals, the follovlng studies are frequently performed J vlth husan subject*: dermal Irritation, seasltltatlon, blood-level de termlast lone, and metabolism.
V* provide fee lilt les and manpower for housing, treating, and observing animals during tests in our fully-staffed, air-conditioned, Mll-equlpped laboratories.
As an Independent laboratory vlth nearly half a century of service Vo Industry and government, roster D. Snell, Inc. clearly recognises the need for confidentiality in all client setters. We are, therefore, prepared to enter Into agreement* providing for control of confidential Information.
A* part of the Boos, Allen family of professional service organi sations, ve offer not only the biological service* In vnicb v* special ise, but also the broad chemical experience of the remainder of the Snell organisation and the extensive engineering, statistical, and manage ment capabilities of the other member* of the Boot, Allen group.
ESTIMATE) TTXt AXP CCOf
The studies can be Initiated vithln JO days of receipt d^ywur authorisation to proceed. In the present outline, vlth no [ oet-sorUs or terminal biochemical studi-s contemplated, the t>lis# vculd be ccsepieted vithln 7 month* of receipt of your authorisation *M the report delivered to you vithln on* month thereafter. Thle le required to permit
o- ; "
? A*'. * *. v ' '-* ' '
.1LuwmHW-ffHjW!
ccnplete end comprehensive analysis of ths data. However, we rsal It# that our projects 0BjAJfX2ATI0tt Of THE VCfOC, Including monthly report*, permits application of prlnclplts of coatlounu revitv *o that you retain control of tb* study. Changss la procedures, protocol*, etc. nay be effected *t sny time, sbortenlrg or lncreaslzg ths duration of th *tudy, adding * recovery phass.stc.
Coet* presented are our best estlx*t*s for performance of tb* entire study with Bolnteoanc* of treated animal* during tb* tin* re quired for report preparation. These are based on tb* time required for the professional and technical staff la plaruilrg, perforalrg, analy sing and reporting tbe experiments and Include the costs of anInals and salerials.
I'
Vs also ask reimbursement for cost* of travel, ccBsamlcatloa. and other expenses Incurred directly la support of this project which are not Included la IKE PROGRAM presented above.
based oa the work outlined In this lstter and experience with itallar project* v* set Last* that the charges for study of sub-
clinical effects of Inorganic lead salt lrgsstloa will rarge frees (.11,000 i to $13,$00.
This estimate will renala unchanged for sixty days, after which tine business conditions nay require charging our estlaate of charges.
ry
It is our practice to operate strictly on a professional service basis with the work standing on its own merits. Any assignment 1* cancellable at any tlna at your discretion without any liability beyond the charges Incurred to the point.
The greet Importance of the study to be carried out Is evident. Ve are keenly Interested In the opportunity to work with you to resolve the open question of potential subcllnlcal effects of lead Irgestloa at levels of 0.33 m* per huan. Application of our substantial capability and experience should yield the solution. Ve are loofcl.'VI forward to receipt of ycur authorization to proceed.
- -1 i
i
' ><ff... s* Sarqj.
.
ruiwjwBWBUAUjiiiAj.. n
*
'
'>
-i
'A
Mr. Doo*ld t c ml*r January 23# 1967 Fig* Bln*
It th*r* ar* *ny qutlon* pltu* do not b*ilt*t to call on u* tad dlacua* th**.
8Lncr*ly your*#
BIOLOGICAL 0CHSCZ LABQRATORUS
Myron S. V*lobrf# Fb.D. Director
R.J. Bouthilet. Rt.O.# Fr**ld*at
"I
&
' '' V
"' '
'.
1;V:" ' ' ~s.. '
r " ' "
'
LIA120A0
Y'-
y
i{
P-
riGURs x
bcxzxxnc DIGRAM OT WADER KAB
i
t
!
;
:
r
t
:. :.
^n*~ ' T*
Y ^*
I,.
I
; - * '
-. '} _ ,
: -x,/*yv%- v* fpuV:'^&f-4r^**-*&"'r-.>.;
N 465.02