alpine fizz and male infertility: a mock trial...1.plaintiffs rumors have been circulating for...

Alpine Fizz and Male Infertility: A Mock Trial

Flora Ichiou HuangBiology and Geo-Science Department

Stuyvesant High SchoolNew York, New York

and

Mona BaumgartenDepartment of Epidemiology and Preventive Medicine

University of MarylandBaltimore, Maryland

The Young Epidemiology Scholars Program (YES) is supported by The Robert Wood Johnson Foundation and administered by the College Board.

ContentsLesson Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Background for Teachers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Appendix 1: Chemical Properties of Tartrazine (Yellow Dye #5) . . . . . . . . . . 19

Appendix 2: Male Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Appendix 3: Criteria for Causation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Appendix 4: Roster of Potential Witnesses . . . . . . . . . . . . . . . . . . . . . . . 27

Appendix 5: Posttrial Worksheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Appendix 6: Epidemiologic Study Designs . . . . . . . . . . . . . . . . . . . . . . . . 32


2Copyright © 2004. All rights reserved.

Lesson Plan

TITLE: Alpine Fizz and Male Infertility: A Mock Trial

SUBJECT AREA: Science (biology or chemistry), social studies, health education

OBJECTIVES: At the end of this module, the students should be able to:

• Be critical in their assessment of claims regarding the risks and benefits of health-relatedproducts and interventions

• Understand what criteria are used when judging whether an observed association is a causalone

• Finish the sentence: “We know something causes something else when . . .”

TIME FRAME: Three to five 45-minute lessons

PREREQUISITE KNOWLEDGE: None, but it may be helpful to have completed some of the othermodules on cohort studies, case-control studies and randomizedcontrolled trials.

MATERIALS NEEDED: Appendices (included at the end of this module)

LINKS TO EDUCATION STANDARDS:

National Science Education:

Unifying Concepts and Processes:

• Evidence, models and explanation

• Change, constancy and measurement

Science as Inquiry

• Abilities necessary to do scientific inquiry

• Understanding about scientific inquiry

Science in Personal and Social Perspectives

• Personal and community health

• Natural and human-induced hazards

3


Copyright © 2004. All rights reserved.

History and Nature of Science

• Science as a human endeavor

• Nature of scientific knowledge

• Historical perspectives

National Health Education Standards:

• Students will demonstrate the ability to access valid health information and health-promoting products and services.

• Students will analyze the influence of culture, media, technology and other factors onhealth.

National Social Studies Standards: To be determined.

Related Internet Sites

Active.com Web site. Available at: http://www.active.com/mtnbiking

Ardmoreite.com Web site. Available at: http://www.ardmoreite.com/stories/032600/liv_abby.shtml

DrWeil.com Web site. Available at: http://www.drweil.com/app/cda/drw_cda.html-command=TodayQA-questionId=3709

Rate It All Web site. Available at: http://www.rateitall.com/item.asp?i=94F1F927-827A-4051-B0D6-20D5E4FC709B

What You Need to Know About Web site. Available at: http://urbanlegends.about.com/library/weekly/aa102799.htm

4



Background for Teachers

RationaleThis module consists of a mock trial resulting from a fictional class action suit brought by 60infertile couples in whom the male was a heavy drinker of Alpine Fizz soft drink. The plaintiffsclaim that the dye in Alpine Fizz (called Yellow Dye #5, or tartrazine) causes low sperm count,resulting in male infertility. Appendix 1 presents a brief summary of tartrazine’s chemical proper-ties and Appendix 2, a brief discussion of male infertility.

In this module, the students will be given a roster of witnesses, with a description of the testi-mony that each witness is prepared to give. The examination and cross-examination of the wit-nesses are expected to elicit, from the students, arguments for and against the possibility of acausal association between Alpine Fizz and infertility.

Students will be assigned to one or more roles in the mock trial. It is expected that the teacherwill tailor this module according to the size of the class and the time available.

Background on CausalityWhen a factor is observed to be associated with a disease or other health-related outcome, thechallenge is to determine whether the factor is a cause of the disease. An observed associationmay be due to chance, it may be due to confounding by another factor or it may have arisenbecause of flaws in study design or execution. Only after these possible explanations have beenconsidered and excluded is it possible to infer that the association may be causal.

For example, it has been found that men who shave less frequently than daily have a higher rateof stroke than men who shave daily. What is not known, however, is whether this is a causalassociation or whether it is due to confounding. Perhaps the men who shave less frequently haveother characteristics (e.g., obesity, smoking) that are related to stroke risk, and it is the overrep-resentation of these characteristics among the men who shave less frequently that makes themappear to have a higher stroke risk.

Another challenge when considering the possibility of a causal association is the issue of tempo-rality. In order for a factor to be a cause of a particular health outcome, it must have precededthe onset of that health outcome. Many times, however, the onset of a health outcome is diffi-cult to pinpoint, and the putative risk factor may actually have occurred after the disease began.Other times, information from cross-sectional studies is inappropriately used to infer causality.For example, one may find that persons with chronic lung disease are less likely to be smokers

5



than persons without the disease. Does this mean that smoking protects from chronic lung dis-ease? No, it may simply reflect the fact that persons who develop chronic lung disease are morelikely to quit smoking after their disease is diagnosed. To provide evidence of causality in such acase, one would have to look at whether smoking preceded the onset of disease. Only cohortstudies and case-control studies that appropriately account for the time order of the exposureand the disease can definitively address this issue.

In 1964 the U.S. Surgeon General released a report entitled Smoking and Health, in which it wasconcluded that “smoking is causally related to lung cancer.” This was a landmark event, markingthe first time that the concept of causality was applied to a major public health problem. Thecriteria used in the report were similar to those proposed by Sir Austin Bradford Hill in 1965.Although Bradford Hill’s criteria are the best known, many authors have adapted his list or createdtheir own. One version of the criteria is shown in Appendix 3. Note that these criteria were notdeveloped to be used as a checklist for evaluating whether a particular association could beinterpreted as causal. Rather, they were meant to help by making explicit the considerations thatare important when inferring causality. For each criterion (except temporality), it is possible tofind at least one example of a causal association that does not meet the criterion.

6



Procedure

1. Assign each student to one or more roles in the mock trial, as shown in Table 1. (Becausethis is a class action suit, students do not need to play the roles of the plaintiffs, only theplaintiffs’ legal team.)

Table 1. Roles to Be Assigned in the Mock Trial

Role Comments

Judge May be the teacher or one of the studentsDecides whether objections are relevant and whether evidence is

admissible, gives instructions to the jury

Defendants Representatives of King Kola, manufacturer of Alpine Fizz

Defense legal team At least two students (may be more, depending on class size)

Plaintiffs Representatives of the 60 men who claim to suffer from infertility related to drinking Alpine Fizz

Plaintiffs’ legal team At least two students (may be more, depending on class size)

Jury Variable number of students, depending on class size

Court reporter Takes notes on proceedings

Witnesses Teacher assigns students to portray witnesses. A student may portray more than one witness, depending on class size.

2. In the pretrial period, the students are given the roster of witnesses with the description ofthe testimony that each witness is prepared to give. The roster and descriptions are summa-rized in the table in Appendix 4, which should be distributed to all students.

3. The teacher distributes the criteria for causation shown in Appendix 3 and reviews themwith the students.

4. The legal teams peruse the roster of witnesses and decide which witnesses they will call.This process should be done with the participation of all the students because it representsone of the most important learning activities of this module. In making the decision aboutwhether to call a witness, the students should discuss whether the witness’s evidence willsupport the plaintiffs or the defendants. Not all potential witnesses have to be chosen. Theteacher may set a limit on the number of witnesses each legal team calls.

7



5. Once the students have decided which witnesses will be called by each legal team, theyshould plan the cross-examination of each of the witnesses by the other side. Throughoutthe process of selecting witnesses, preparing testimony and preparing cross-examination,the teacher should verify that the students understand why the evidence is supportive ofone side or the other and what principles are demonstrated (see Table 2), using the criteriafor causation as a guide.

6. The teacher may assign one or more students to be the court reporter. Alternatively, theteacher may ask the students who assume the roles of witnesses to write a summary of thetestimony they would give if called as a witness, and may ask the students who are mem-bers of the legal teams to write a summary of their examination and cross-examination.

Procedures continue on page 17.

8



9



Tabl

e 2.

Witn

ess

Rost

er (

Teac

her’s

Ver

sion)

*

Wit

ness

for

Pr

inci

ples

W

hich

Sid

e?Cr

oss-

Exam

inat

ion

Argu

men

tsDe

mon

stra

ted

1.Pl

aint

iffs

Rum

ors

have

bee

n ci

rcul

atin

g fo

r se

vera

l yea

rsre

lati

ng t

o th

e dy

e ca

lled

FD&

C Ye

llow

No.

5,

scie

ntifi

cally

kno

wn

as T

artr

azin

e bu

t co

mm

only

calle

d Ye

llow

Dye

#5

in A

lpin

e Fi

zz t

o lo

w s

perm

coun

ts in

men

who

con

sum

e th

e ch

artr

euse

-col

-or

ed d

rink.

Sev

eral

cha

t ro

oms

post

mes

sage

s th

atpu

t fo

rwar

d th

e be

lief

that

you

ng m

en’s

fert

ility

,se

xual

att

ract

iven

ess

or s

exua

l pot

ency

cou

ld b

ead

vers

ely

affe

cted

by

drin

king

Alp

ine

Fizz

. Fo

r th

epu

rpos

es o

f th

is e

xerc

ise,

let

us im

agin

e th

at a

grou

p of

hea

vy A

lpin

e Fi

zz d

rinke

rs m

et in

one

of

thes

e ch

at r

oom

s an

d di

scov

ered

tha

t th

ey w

ere

all h

avin

g tr

oubl

e w

ith

fert

ility

. Al

l wer

e m

arrie

d,al

l had

bee

n tr

ying

uns

ucce

ssfu

lly t

o ge

t th

eir

wiv

es p

regn

ant

for

mor

e th

an o

ne y

ear,

and

all

dran

k at

leas

t th

ree

cans

of

Alpi

ne F

izz

ever

y da

y.Th

ey la

unch

ed a

Web

sit

e an

d ur

ged

peop

le w

ith

the

sam

e pr

oble

m t

o co

mm

unic

ate

wit

h th

em.

Afte

r ab

out

a ye

ar t

hey

had

asse

mbl

ed a

bout

60

cou

ples

wit

h in

fert

ility

pro

blem

s th

at t

hey

attr

ibut

ed t

o th

e m

en’s

drin

king

of

Alpi

ne F

izz.

They

hire

d an

impr

essi

ve le

gal t

eam

and

file

d a

clas

s ac

tion

suit

.

2.De

fend

ant

The

man

ufac

ture

r of

Alp

ine

Fizz

, Ki

ng K

ola,

clai

ms

that

the

re i

s ab

solu

tely

no

scie

ntifi

c

Plai

ntiff

s

Defe

ndan

t

•Ch

ance

•Co

nfou

ndin

g

•An

ecdo

te•

No c

ompa

ri-so

n gr

oup

The

fact

tha

t so

me

men

drin

k Al

pine

Fizz

and

bec

ome

infe

rtile

doe

s no

tne

cess

arily

mea

n th

at t

here

is a

caus

al a

ssoc

iati

on.

Mill

ions

of

peop

ledr

ink

Alpi

ne F

izz

and

mill

ions

of

peop

le a

re in

fert

ile,

and

it is

to

beex

pect

ed t

hat

som

e pe

ople

who

drin

k Al

pine

Fiz

z w

ill a

lso

be in

fer-

tile

. Ev

en if

it is

not

a c

oinc

iden

ce,

the

asso

ciat

ion

may

be

the

resu

lt o

fco

nfou

ndin

g by

a t

hird

fac

tor

(e.g

.,en

gagi

ng in

ext

rem

e sp

orts

, us

e of

recr

eati

onal

dru

gs).

For

exa

mpl

e,m

en w

ho u

se r

ecre

atio

nal d

rugs

(som

e of

whi

ch c

an,

it is

bel

ieve

d,lo

wer

spe

rm c

ount

s) m

ay a

lso

bem

ore

likel

y to

drin

k Al

pine

Fiz

z,cr

eati

ng a

n ap

pare

nt (

but

not

caus

al)

asso

ciat

ion

betw

een

Alpi

neFi

zz a

nd lo

w s

perm

cou

nts.

Ther

e ar

e at

leas

t 60

men

who

beca

me

infe

rtile

aft

er d

rinki

ng la

rge

quan

titi

es o

f Al

pine

Fiz

z, a

nd t

here

cont

inue

10



Wit

ness

for

Pr

inci

ples

W

hich

Sid

e?Cr

oss-

Exam

inat

ion

Argu

men

tsDe

mon

stra

ted

evid

ence

tha

t ta

rtra

zine

, ca

ffei

ne,

or a

ny o

ther

subs

tanc

e fo

und

in A

lpin

e Fi

zz i

s re

late

d to

infe

rtili

ty.

All o

f th

e so

ft d

rink’

s in

gred

ient

s ar

eap

prov

ed b

y th

e Fo

od a

nd D

rug

Adm

inis

trat

ion

(FDA

), t

he f

eder

al a

genc

y th

at r

egul

ates

suc

hm

atte

rs.

The

man

ufac

ture

r cl

aim

s th

at t

he f

act

that

som

e m

en d

rink

Alpi

ne F

izz

and

are

infe

rtile

is s

impl

y co

inci

denc

e an

d th

at t

here

is

no c

ausa

las

soci

atio

n be

twee

n th

e tw

o.

3.H

arry

G. W

alke

rM

r. W

alke

r is

an

80-y

ear-

old

man

who

dra

nkAl

pine

Fiz

z al

l his

life

and

con

tinu

es t

o co

nsum

eat

leas

t tw

o bo

ttle

s a

day.

He

has

fath

ered

12

chi

ldre

n an

d is

pre

pare

d to

tes

tify

tha

t hi

sso

ft d

rink

cons

umpt

ion

has

had

no e

ffec

t on

his

fert

ility

.

4. M

ary

Stew

art-

Swan

son

Ms.

Ste

war

t-Sw

anso

n ow

ns M

ary’

s De

li in

Sprin

gfie

ld,

Conn

ecti

cut.

Aft

er a

few

mon

ths

ofdr

inki

ng la

rge

quan

titi

es o

f Al

pine

Fiz

z (m

ore

than

fou

r ca

ns p

er d

ay)

she

bega

n ha

ving

num

er-

ous

sym

ptom

s, in

clud

ing

rash

, di

arrh

ea a

ndsh

ortn

ess

of b

reat

h. S

he is

pre

pare

d to

tes

tify

th

at a

fter

she

sto

pped

drin

king

Alp

ine

Fizz

, al

lhe

r sy

mpt

oms

disa

ppea

red.

Defe

ndan

t

Plai

ntiff

s

•An

ecdo

te•

Exce

ptio

ns d

ono

t in

vali-

date

the

rul

e•

Tem

pora

lity

•An

ecdo

te•

Anal

ogy

•Ch

ance

are

man

y m

ore

who

hav

e vi

site

d th

eW

eb s

ite.

In

som

e ca

ses

men

who

stop

ped

drin

king

Alp

ine

Fizz

alm

ost

imm

edia

tely

reg

aine

d th

eir

fert

ility

.

The

fact

tha

t on

e m

an h

as c

onsu

med

larg

e qu

anti

ties

of

the

drin

k an

d ha

sm

aint

aine

d a

high

leve

l of

fert

ility

does

not

neg

ate

the

poss

ibili

ty t

hat

Alpi

ne F

izz

caus

es in

fert

ility

in m

ost

men

. Be

caus

e M

r. W

alke

r is

80

year

sol

d an

d Al

pine

Fiz

z di

d no

t be

com

ew

idel

y av

aila

ble

unti

l the

196

0s,

mos

t or

all

of h

is A

lpin

e Fi

zz c

on-

sum

ptio

n m

ust

have

occ

urre

d af

ter

his

child

ren

wer

e bo

rn.

The

fact

tha

t on

e w

oman

has

con

-su

med

larg

e qu

anti

ties

of t

he d

rink

and

has

expe

rienc

ed s

ympt

oms

such

as t

hese

doe

s no

t pr

ove

that

the

drin

k w

as t

he c

ause

of

the

sym

ptom

s.Th

ese

sym

ptom

s ar

e qu

ite

com

mon

,an

d it

may

be

coin

cide

nce

that

the

sym

ptom

s ap

pear

ed a

fter

the

wom

anst

arti

ng d

rinki

ng la

rge

amou

nts

ofAl

pine

Fiz

z an

d di

sapp

eare

d af

ter

she

cont

inue

11



5.Gr

egor

y M

arch

ildon

Mr.

Mar

child

on is

a M

adis

on,

Wis

cons

in,

man

who

clai

ms

he is

sur

e th

at A

lpin

e Fi

zz lo

wer

s sp

erm

coun

t. H

e is

pre

pare

d to

tes

tify

tha

t he

alw

ays

drin

ks A

lpin

e Fi

zz b

efor

e in

terc

ours

e an

d no

ne o

fhi

s se

xual

par

tner

s ha

s ev

er b

ecom

e pr

egna

nt.

6.M

iche

lle C

aban

oM

s. C

aban

o is

an

exec

utiv

e at

Bor

nste

in,

Burr

ard,

Bens

on a

nd C

aban

o, a

wel

l-kn

own

New

Yor

k Ci

tyad

vert

isin

g ag

ency

. Sh

e de

velo

ped

the

adve

rtis

ing

cam

paig

n lin

king

Alp

ine

Fizz

to

extr

eme

spor

ts.

Som

e of

the

se s

port

s (e

.g.,

dirt

bik

ing,

mot

ocro

ss,

mou

ntai

n bi

king

) ar

e re

pute

d to

cau

se lo

w s

perm

coun

t in

men

. She

is p

repa

red

to t

esti

fy t

hat

itm

ay b

e th

at m

en w

ho e

ngag

e in

the

se s

port

s ar

em

ore

likel

y th

an o

ther

s to

drin

k Al

pine

Fiz

z an

dth

at it

is t

he s

port

s ac

tivi

ty,

not

the

Alpi

ne F

izz,

that

is t

he c

ause

of

the

infe

rtili

ty.

7.La

szlo

Nag

yM

r. Na

gy is

the

Chi

ef E

xecu

tive

Off

icer

of

ABC

Chem

ical

s, a

New

Jer

sey

com

pany

tha

t m

anuf

ac-

ture

s dy

es (

incl

udin

g Ye

llow

Dye

#5)

, ar

tific

ial

flavo

rings

and

oth

er c

hem

ical

s fo

r th

e fo

od

Plai

ntiff

s

Defe

ndan

t

Defe

ndan

t

•An

ecdo

te•

Exce

ptio

ns d

ono

t in

valid

ate

the

rule

•Co

nfou

ndin

g

•Ab

senc

e of

evid

ence

doe

sno

t m

ean

abse

nce

ofas

soci

atio

n

stop

ped

drin

king

Alp

ine

Fizz

. In

any

case

it is

kno

wn

that

tar

traz

ine

can

caus

e al

lerg

ic r

eact

ions

in s

ome

peop

le. Th

is f

act

is n

ot r

elev

ant

toth

e qu

estio

n of

whe

ther

tar

traz

ine

caus

es m

ale

infe

rtili

ty, as

the

bio

log-

ical

mec

hani

sm le

adin

g to

alle

rgy

isqu

ite

diff

eren

t fro

m t

hat

lead

ing

toin

fert

ility

.

The

fact

tha

t on

e m

an r

egul

arly

con

-su

mes

the

drin

k be

fore

int

erco

urse

and

has

neve

r im

preg

nate

d an

yone

does

not

pro

ve t

hat

Alpi

ne F

izz

caus

es i

nfer

tilit

y.

The

link

betw

een

extr

eme

spor

ts a

ndin

fert

ility

is t

enuo

us a

nd b

ased

on

little

scie

ntifi

c ev

iden

ce.

The

fact

tha

t th

ere

has

neve

r be

en a

repo

rt o

f Al

pine

Fiz

z–re

late

d in

fer-

tilit

y do

es n

ot m

ean

that

suc

h a

cond

itio

n do

es n

ot e

xist

.

cont

inue

12



Wit

ness

for

Pr

inci

ples

W

hich

Sid

e?Cr

oss-

Exam

inat

ion

Argu

men

tsDe

mon

stra

ted

indu

stry

. He

is p

repa

red

to t

esti

fy t

hat

mor

e th

antw

o m

illio

n po

unds

of

tart

razi

ne a

re u

sed

ever

yye

ar in

med

icin

es,

beve

rage

s, d

esse

rts,

pro

cess

edve

geta

bles

and

cos

met

ics.

Bec

ause

a 1

986

FDA

advi

sory

com

mit

tee

conc

lude

d th

at Y

ello

w D

ye #

5ca

n ca

use

alle

rgic

ski

n re

acti

ons

(suc

h as

hiv

esan

d ra

shes

), m

anuf

actu

rers

who

use

tar

traz

ine

mus

t lis

t it

on

thei

r la

bels

. Ho

wev

er,

Mr.

Nagy

will

tes

tify

tha

t th

ere

has

neve

r be

en a

ny e

vi-

denc

e th

at t

he d

ye is

rel

ated

to

mal

e in

fert

ility

.

8.Pa

tric

k L.

Rod

rigu

ezM

r. Ro

drig

uez

is a

rep

rese

ntat

ive

of t

he A

mer

ican

Caff

eine

Fou

ndat

ion.

He

is p

repa

red

to t

esti

fyth

at a

ltho

ugh

Alpi

ne F

izz

cont

ains

ver

y hi

ghle

vels

of

caff

eine

(hi

gher

tha

n ei

ther

Col

a Ri

teor

Kin

g Ko

la),

the

re is

evi

denc

e to

sug

gest

tha

tca

ffei

ne a

ctua

lly in

crea

ses

the

mot

ility

and

eff

ec-

tive

ness

of

sper

m c

ells

.

9.Ja

net

S. F

ang

Ms.

Fan

g is

Vic

e Pr

esid

ent

for

Publ

ic A

ffairs

for

the

Soft

Drin

k M

anuf

actu

rers

Ass

ocia

tion

of A

mer

ica.

She

is p

repa

red

to t

estify

tha

t Al

pine

Fiz

z ha

sbe

en c

onsu

med

by

mill

ions

of

peop

le s

ince

the

drin

k w

as f

irst

intr

oduc

ed in

the

195

0s a

nd y

etKi

ng K

ola

has

neve

r re

ceiv

ed a

con

sum

er in

quiry

or

com

plai

nt a

bout

the

effec

ts o

f Al

pine

Fiz

z on

mal

efe

rtili

ty o

r po

tenc

y. H

er t

estim

ony

will

be

base

d on

the

prem

ise

that

if t

here

wer

e su

ch e

ffec

ts t

hey

wou

ld h

ave

beco

me

appa

rent

by

now.

Defe

ndan

t

Defe

ndan

t

•Ir

rele

vant

info

rmat

ion

•Ab

senc

e of

evid

ence

does

not

mea

nab

senc

e of

asso

ciat

ion

This

tes

tim

ony

is ir

rele

vant

bec

ause

the

plai

ntiff

s be

lieve

it is

the

dye

,no

t th

e ca

ffei

ne,

that

is t

he c

ulpr

it.

The

fact

tha

t th

ere

has

neve

r be

en a

repo

rt o

f Al

pine

Fiz

z–re

late

d in

fert

il-it

y do

es n

ot m

ean

that

suc

h a

con-

diti

on d

oes

not

exis

t.

cont

inue

13



10.V

anes

sa J

ohns

on, P

h.D.

Dr

. Jo

hnso

n is

an

orga

nic

chem

ist

who

spe

cial

izes

in d

yes.

Sh

e w

ill t

esti

fy t

hat

the

chem

ical

str

uc-

ture

of

tart

razi

ne (

com

mon

ly k

now

n as

Yel

low

Dye

#5)

is s

imila

r to

tha

t of

oth

er d

yes,

som

e of

whi

ch a

re k

now

n to

cau

se in

fert

ility

or

carc

ino-

gene

sis.

She

will

als

o di

scus

s so

me

of t

he o

ther

heal

th e

ffec

ts (

e.g.

, al

lerg

y) o

f Ye

llow

Dye

#5.

11.P

raga

ti D

esai

, Ph.

D.Dr

. De

sai i

s a

toxi

colo

gist

who

stu

dies

the

car

-ci

noge

nic

effe

cts

of a

rtifi

cial

dye

s on

ani

mal

s.Sh

e ha

s al

so s

tudi

ed t

he e

ffec

ts t

hat

othe

r ch

em-

ical

s ha

ve o

n in

fert

ility

.

12.R

oger

Dav

is, M

.D.,

Ph.D

.Dr

. Da

vis

is a

phy

sici

an w

ho is

an

expe

rt o

n fe

r-ti

lity.

He

is p

repa

red

to t

esti

fy t

hat

he h

as n

ever

enco

unte

red

a ca

se o

f Al

pine

Fiz

z–re

late

d in

fert

il-it

y in

his

pra

ctic

e.

13.G

reg

Mar

kow

icz,

DrP

HDr

. Mar

kow

icz

is a

n ep

idem

iolo

gist

who

has

stu

died

men

who

don

ate

sper

m a

t a

sper

m b

ank.

In

his

stud

y Dr

. Mar

kow

icz

aske

d sp

erm

don

ors

to c

om-

plet

e a

ques

tionn

aire

, and

one

of

the

ques

tions

aske

d w

heth

er t

hey

dran

k Al

pine

Fiz

z. H

is f

indi

ngs

indi

cate

tha

t m

en w

ho d

rank

one

to

two

20-o

z.bo

ttle

s of

Alp

ine

Fizz

per

day

had

a s

igni

fican

tlylo

wer

spe

rm c

ount

tha

n m

en w

ho d

rank

Alp

ine

Fizz

less

fre

quen

tly. M

en w

ho d

rank

thr

ee o

r m

ore

bot-

tles

per

day

had

an e

ven

low

er s

perm

cou

nt.

Plai

ntiff

s

Plai

ntiff

s

Defe

ndan

t

Plai

ntiff

s

•An

alog

y

•An

alog

y•

Diff

icul

ty in

extr

apol

atin

gre

sults

of a

ni-

mal

stu

dies

to h

uman

s•

Abse

nce

ofev

iden

ce d

oes

not

mea

nab

senc

e of

asso

ciat

ion

•Co

nfou

ndin

g•

Tem

pora

lity

•Bi

olog

ical

grad

ient

The

fact

tha

t ot

her

dyes

cau

se in

fer-

tilit

y do

es n

ot m

ean

Yello

w D

ye #

5do

es.

Even

tho

ugh

Yello

w D

ye #

5m

ay c

ause

oth

er c

ondi

tion

s, it

doe

sno

t m

ean

it a

lso

caus

es in

fert

ility

.

The

fact

tha

t so

me

dyes

hav

e be

enfo

und

to c

ause

can

cer

or in

fert

ility

inan

imal

s do

es n

ot p

rove

tha

t Ye

llow

Dye

#5 c

ause

s in

fert

ility

in m

en.

The

fact

tha

t Dr

. Da

vis

has

neve

rob

serv

ed a

rel

atio

n be

twee

n Al

pine

Fizz

and

infe

rtili

ty in

his

pra

ctic

edo

es n

ot m

ean

that

suc

h an

ass

ocia

-ti

on d

oes

not

exis

t. H

e m

ay s

impl

yne

ver

have

ask

ed h

is p

atie

nts

abou

tAl

pine

Fiz

z co

nsum

ptio

n.

The

fact

tha

t th

ose

who

dra

nk a

lot

of A

lpin

e Fi

zz h

ad lo

wer

spe

rm c

ount

may

be

due

to s

ome

othe

r ch

arac

ter-

isti

c (a

con

foun

ding

var

iabl

e) t

hat

isas

soci

ated

wit

h bo

th A

lpin

e Fi

zz a

ndsp

erm

cou

nt.

Also

, th

ere

is n

o in

for-

mat

ion

abou

t ti

min

g. I

t m

ay b

e th

atm

en b

egan

drin

king

Alp

ine

Fizz

aft

erth

ey b

egan

to

have

low

er s

perm

coun

t. I

f so

, Al

pine

Fiz

z ca

nnot

be

caus

ally

rel

ated

to

low

spe

rm c

ount

.

cont

inue

14



Wit

ness

for

Pr

inci

ples

W

hich

Sid

e?Cr

oss-

Exam

inat

ion

Argu

men

tsDe

mon

stra

ted

14.G

illia

n M

cDer

mot

t, P

h.D.

Dr.

McD

erm

ott

is a

n ep

idem

iolo

gist

who

has

don

ea

stud

y on

pat

ient

s at

a f

erti

lity

clin

ic.

She

foun

dth

at t

he m

en in

her

stu

dy w

ho d

rank

one

or

mor

e12

-oz.

can

s of

Alp

ine

Fizz

per

day

had

an

aver

age

sper

m c

ount

sim

ilar

to t

hat

of m

en w

ho d

rank

Alpi

ne F

izz

less

fre

quen

tly.

15. L

uz R

iver

a, P

h.D.

Dr. R

iver

a is

a c

linic

al p

sych

olog

ist

who

will

tes

tify

that

in h

er e

xper

ienc

e, m

en w

ho b

ecom

ede

pres

sed

as a

res

ult

of in

fert

ility

may

tur

n to

stim

ulan

ts (

such

as

Alpi

ne F

izz)

to

com

pens

ate

for

thei

r fe

elin

gs o

f de

pres

sion

.

16.J

ohn

Thom

pson

Mr.

Thom

pson

is a

n ac

tivi

st w

ho s

et u

p a

Web

site

tha

t co

llect

s th

e st

orie

s of

men

who

dra

nkAl

pine

Fiz

z an

d be

cam

e in

fert

ile a

s a

resu

lt.

17.H

arry

Hum

phre

yM

r. Hu

mph

rey

is a

n he

rbal

ist

who

bel

ieve

s th

atal

l syn

thet

ic c

hem

ical

s, in

clud

ing

Yello

w D

ye #

5,ar

e ha

zard

ous

to h

ealth.

Defe

ndan

t

Defe

ndan

t

Plai

ntiff

s

Plai

ntiff

s

•Se

lect

ion

bias

•Te

mpo

ralit

y

•An

ecdo

te•

Sele

ctio

nbi

as•

No c

ompa

ri-so

n gr

oup

•Ir

rele

vant

info

rmat

ion

•Pe

rson

alop

inio

n

Beca

use

this

stu

dy w

as d

one

amon

gpa

tien

ts a

t a

fert

ility

clin

ic,

the

men

may

hav

e ha

d a

low

er s

perm

cou

nton

ave

rage

tha

n th

e ge

nera

l pop

ula-

tion

. Th

eref

ore,

all

the

men

in t

his

stud

y, r

egar

dles

s of

the

ir Al

pine

Fiz

zdr

inki

ng h

abit

s, m

ay h

ave

had

low

sper

m c

ount

, w

hich

wou

ld m

ake

itha

rder

to

dete

ct a

diff

eren

cebe

twee

n th

e Al

pine

Fiz

z dr

inke

rs a

ndno

ndrin

kers

, ev

en if

suc

h an

ass

ocia

-ti

on e

xist

ed.

Ther

e is

no

scie

ntifi

c ev

iden

ce t

oco

nfirm

her

sta

tem

ents

.

The

Web

sit

e as

ks o

nly

for

men

who

dran

k Al

pine

Fiz

z an

d be

cam

e in

fer-

tile

. It

doe

s no

t as

k fo

r m

en w

hodr

ank

Alpi

ne F

izz

and

did

not

beco

me

infe

rtile

.

This

is ir

rele

vant

.

cont

inue

15



18.F

ranz

Lic

hter

, M.D

.Dr

. Li

chte

r, a

Swis

s ra

diol

ogis

t, h

as d

one

a st

udy

com

parin

g m

ale

mou

ntai

n bi

kers

wit

h m

en w

hoar

e no

t m

ount

ain

bike

rs.

He is

pre

pare

d to

tes

tify

that

mou

ntai

n bi

kers

hav

e a

low

er s

perm

cou

ntan

d le

ss m

otile

spe

rm t

han

men

who

are

not

mou

ntai

n bi

kers

, an

d th

at m

ount

ain

bike

rs a

rem

ore

likel

y to

hav

e ab

norm

alit

ies

in t

heir

scro

-tu

m.

He b

elie

ves

that

the

obs

erve

d in

fert

ility

amon

g th

e pl

aint

iffs

may

be

due

to t

heir

part

ici-

pati

on in

ext

rem

e sp

orts

(w

hich

is m

ore

com

mon

amon

g m

en w

ho d

rink

Alpi

ne F

izz)

rat

her

than

to

the

drin

k it

self.

19.G

eorg

eann

e Pa

rker

, Ph.

D.Dr

. Pa

rker

is a

n ep

idem

iolo

gist

who

has

com

pile

dst

atis

tics

on

aver

age

sper

m c

ount

s am

ong

U.S.

mal

es d

urin

g ev

ery

year

bet

wee

n 19

71 a

nd 2

001.

She

also

has

sta

tist

ics

on t

he a

vera

ge a

nnua

l per

capi

ta c

onsu

mpt

ion

of A

lpin

e Fi

zz in

the

Uni

ted

Stat

es d

urin

g th

e sa

me

perio

d. H

er s

tati

stic

scl

early

dem

onst

rate

tha

t sp

erm

cou

nts

decl

ined

and

Alpi

ne F

izz

cons

umpt

ion

incr

ease

d ov

er t

hepe

riod

in q

uest

ion.

Defe

ndan

t

Plai

ntiff

s

•Co

nfou

ndin

g

•Co

nfou

ndin

g•

Tem

pora

lity

•Ec

olog

ic

falla

cy

Havi

ng lo

w s

perm

cou

nt o

r lo

wsp

erm

mot

ility

doe

s no

t m

ake

itim

poss

ible

to

conc

eive

. Al

so,

ther

e is

no e

vide

nce

that

Alp

ine

Fizz

drin

kers

are

in f

act

mor

e lik

ely

to e

ngag

e in

extr

eme

spor

ts.

Mea

n sp

erm

cou

nt a

nd m

ean

per

capi

ta c

onsu

mpt

ion

of A

lpin

e Fi

zzar

e ag

greg

ate

stat

isti

cs,

base

d on

an e

ntire

pop

ulat

ion.

Thi

s ty

pe o

fda

ta c

anno

t be

use

d to

inf

er r

ela-

tion

ship

s on

the

ind

ivid

ual

leve

l.(I

t is

cal

led

ecol

ogic

fal

lacy

whe

nag

greg

ate

data

are

use

d to

inf

erre

lati

onsh

ips

on t

he i

ndiv

idua

lle

vel.)

The

fac

t th

at A

lpin

e Fi

zzco

nsum

ptio

n in

crea

sed

in t

he U

.S.

popu

lati

on d

oes

not

mea

n th

at i

tin

crea

sed

amon

g m

en w

ho w

ere

atri

sk o

f be

com

ing

infe

rtile

. Be

side

s,th

ere

are

man

y fa

ctor

s ot

her

than

Alpi

ne F

izz

cons

umpt

ion

that

chan

ged

over

the

tim

e pe

riod

and

that

may

be

the

caus

e of

the

low

er

cont

inue

16



Wit

ness

for

Pr

inci

ples

W

hich

Sid

e?Cr

oss-

Exam

inat

ion

Argu

men

tsDe

mon

stra

ted

20.A

nato

ly P

rito

vich

, Ph.

D.Dr

. Pr

itov

ich

is a

rep

rodu

ctiv

e bi

olog

ist.

He

will

test

ify t

hat

the

sper

m c

ount

is a

mea

sure

of

the

tota

l num

ber

of s

perm

pre

sent

in a

man

’s se

men

,us

ually

rec

orde

d in

mill

ions

of

sper

m p

er m

illili

ter

of s

emen

. Sp

erm

cou

nt v

arie

s w

idel

y am

ong

hum

an m

ales

. A

norm

al c

ount

is r

egar

ded

asbe

ing

grea

ter

than

20

mill

ion/

ml.

A m

an is

con

-si

dere

d at

ris

k of

bei

ng in

fert

ile if

his

spe

rmco

unt

is le

ss t

han

20 m

illio

n/m

l of

sem

en.

How

ever

, so

me

men

wit

h lo

w s

perm

cou

nts

are

fert

ile,

whe

reas

oth

ers

wit

h hi

gher

cou

nts

prov

eto

be

infe

rtile

. Dr

. Pr

itov

ich

will

tes

tify

tha

t a

mea

sure

of

sper

m c

ount

is n

ot a

com

plet

ely

reli-

able

met

hod

of a

sses

sing

fer

tilit

y.

Defe

ndan

t•

Outc

ome

def-

init

ion

and

mea

sure

men

t•

Diff

icul

ty in

dete

ctin

gef

fect

s w

hen

back

grou

ndva

riabi

lity

ishi

gh

sper

m c

ount

s. A

lso,

it

is i

mpo

ssib

lew

ith

thes

e da

ta t

o as

cert

ain

that

Alpi

ne F

izz

cons

umpt

ion

prec

eded

low

erin

g of

the

spe

rm c

ount

.

Alth

ough

som

e m

en w

ith

low

spe

rmco

unt

are

fert

ile a

nd s

ome

men

wit

hhi

gh s

perm

cou

nt a

re in

fert

ile,

it is

clea

r th

at a

man

wit

h lo

w s

perm

coun

t is

mor

e lik

ely

to b

e in

fert

ileth

an a

man

wit

h hi

gher

spe

rm c

ount

.

*The

tea

cher

sho

uld

caut

ion

stud

ents

tha

t al

l of

the

indi

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Procedures (continued) from page 8.

7. Before proceedings begin, the judge sets the stage by explaining the importance of assess-ing causality in a complex world. The judge explains that the fundamental question the jurymust answer in this case is whether drinking Alpine Fizz causes male infertility. The judgeinstructs the jury to disregard any preconceptions they might have about the issue at hand.The fact that many consider the association between Alpine Fizz and infertility to be anurban legend does not exclude the possibility that there is in fact a causal association.(However, the teacher should warn students that Alpine Fizz should not be used as amethod of contraception.)

8. The mock trial takes place, with each side having the opportunity to call its witnesses. Eachwitness called may be cross-examined by the other side.

9. The jury deliberates, reaches a verdict, and announces its verdict.

10. The verdict is discussed by all students in the class. (The teacher may use the worksheet inAppendix 5 to structure this discussion.) The teacher asks the class to assess how likely it isthat the correct verdict has been reached. Do the students believe, on the basis of the evi-dence, that Alpine Fizz causes male infertility? If the losing side were to appeal the verdict,what further evidence would it like to have? The teacher could, at this stage, introduce thecriteria for causation listed in Appendix 3.

11. The teacher points out that the example used in this mock trial is hypothetical. Court casesfollow legal rules for determining causality that are appropriate for the goals of the litiga-tion but are not necessarily consistent with the principles of the scientific method.However, epidemiologists, health care providers and policymakers, as well as students, areregularly faced with the challenge of deciding whether a particular association is a causalone. The teacher may at this point review the types of studies that are often used by epi-demiologists when they are exploring the possibility of an association between an exposureand a disease. Appendix 6 gives a very brief overview of epidemiologic study designs andthe potential of each to shed light on causal associations.

12. It is important to complete this module by giving the students a realistic example of thedifficult process of assessing whether there is a causal association between an exposure anda disease. The association between smoking and lung cancer is such an example. We recom-mend that the students be asked to read the section (pages 54–69) on tobacco and lungcancer in the book Investigating Disease Patterns: The Science of Epidemiology, by P. D. Stolley and T. Lasky (New York: Scientific American Library; 1998).

13. Ask the students to finish the sentence: “We know something causes something elsewhen . . .”

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Assessment

1. Ask students the following question:

It is now universally accepted that cigarette smoking is causally related to lung cancer.Review pages 54 to 69 in the book Investigating Disease Patterns: The Science ofEpidemiology, by P. D. Stolley and T. Lasky (New York: Scientific American Library; 1998),which describes how that causal association was established.

Now imagine that you were given an unlimited amount of funding to put together a teamof scientists including, among others, biologists, chemists, and epidemiologists. The objec-tive of the team is to determine if there is an association between Alpine Fizz anddecreased sperm count and, if there is, whether it is causal. How would you go about doingthis? Answer this question using what you learned from reading the passage from Stolleyand Lasky’s book, as well as what you have learned in your science classes. Provide an out-line of the different types of studies that you would use and explain your choices. Specifywhich study you would conduct first and give a logical sequence of the studies that wouldfollow. If you use human participants in your studies, what are some ethical issues that youmust consider when designing these studies?


Look closely at the criteria for causation. For each criterion, think about whether this is anecessary condition for causation. For example, is it necessary for a causal association todisplay a biological gradient? For each criterion, see whether you can think of a situation inwhich an association could be causal even though it does not meet the criterion.


The Internet has made it easier for all types of urban legends to spread. Have you heard orread about asbestos in tampons or antiperspirants causing breast cancer? A description ofthese rumors and urban legends can be found at Web sites such as Hoaxbusters, available athttp://hoaxbuster.ciac.org. What are the potential social and health consequences of suchurban legends? What is an appropriate reaction when hearing or reading about a health riskor a health benefit? How can you decide if what you have heard or read is in fact an urbanlegend?

4. Give students an article from the popular press (e.g., Time or Newsweek) about the evidencethat a particular exposure (e.g., cell phone use) may cause a particular outcome (e.g., braincancer). Identify statements in the article that describe evidence for causation. Ask stu-dents to alter the statements in a way that would make the evidence more persuasive andin a way that would make the evidence less persuasive.

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Appendix 1: Chemical Properties of Tartrazine

(Yellow Dye #5)

19



Common name Tartrazine

Suggested name Tartrazine

Other names

C.I. number 19140

C.I. name Acid yellow 23

Class Azo

Ionisation Acid

Solubility in water Soluble

Solubility in ethanol Sparing

Absorption maximum 425

Colour Yellow

Empirical formula C16H9N4O9S2Na3

Formula weight 534.385

Structural formula:

Tartrazine is often used saturated in cellosolve (2-ethoxy ethanol) to differentiate other aciddyes while counterstaining the tissues yellow. Lendrum’s phloxine tartrazine method for Panethcell granules is a good example. It is rarely used for other purposes.

N

HO

N

N

N

SO3Na

COONa

NaO3S

References:

Conn’s Biological StainsR. D. Lillie.Williams & Wilkins, Baltimore, MD, U.S.A.

The Merck Index, 12 ed.Susan Budavari, Ed.Merck & Co., NJ, USA.

Aldrich chemical catalogueAldrich, Milwaukee, WI, USA.

Source: StainsFile Web site. Available at: http://members.pgonline.com/~bryand/StainsFile/dyes/19140.htm

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Appendix 2: Male Infertility

What is infertility?Infertility is defined by the American Society for Reproductive Medicine (ASRM) as a disease ofthe reproductive system that impairs the body’s ability perform the basic function of reproduc-tion. Although conceiving a child may seem to be simple and natural, the physiological processis quite complicated and depends on the proper function of many factors, including the follow-ing, as listed by the ASRM:

• production of healthy sperm by the man

• production of healthy eggs by the woman

• unblocked fallopian tubes that allow the sperm to reach the egg

• the sperm’s ability to fertilize the egg

• the ability of the fertilized egg to become implanted in the uterus

• adequate embryo quality

Who is affected by infertility?The average chance to conceive for a normally fertile couple having regular, unprotected inter-course is approximately 25 percent during each menstrual cycle. In most couples, conceptionoccurs within about 12 months. However, infertility affects about 10 percent of couples of child-bearing age. Infertility is not just a woman’s concern. A problem with the male is the sole cause,or a contributing cause, of infertility in about 40 percent of infertile couples. About one-fourthof infertile couples have more than one cause or factor related to their inability to conceive.About 10 to 15 percent of couples have no identifiable cause for their infertility after medicalinvestigation.

What are the risk factors for men regarding infertility?The following is a list of risk factors related to male infertility (also called male factor or malefactor infertility):

• history of prostatitis or genital infection

• testicular trauma or torsion

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• history of precocious puberty (puberty occurring at a young age) or delayed puberty(puberty occurring at an older age)

• exposure to toxic substances or hazards on the job, such as lead, cadmium, mercury,ethylene oxide, vinyl chloride, radioactivity, and x-rays

• cigarette or marijuana smoke

• heavy alcohol consumption

• exposure of the genitals to high temperatures

• hernia repair

• undescended testicles

• prescription drugs for ulcers or psoriasis

• DES taken by mother during pregnancy

• mumps after puberty

What causes male factor infertility?The main causes of male infertility can be divided into the following categories:

• Sperm disorders: Problems with the production and maturation of sperm are the most com-mon causes of male infertility. Sperm may be immature, abnormally shaped, or unable tomove properly. Or, normal sperm may be produced in abnormally low numbers (oligospermia)or seemingly not at all (azoospermia). This problem may be caused by many different condi-tions, including the following:

• Infectious diseases or inflammatory conditions such as the mumps virus

• Endocrine or hormonal disorders such as Kallmann’s syndrome or pituitary problem

• Immunological disorders in which some men produce antibodies to their own sperm

• Environmental and lifestyle factors

• Genetic diseases (most are associated with sperm abnormalities, either directly orindirectly):

– Cystic fibrosis: An inherited condition that typically involves the lungs and pancreas, butcan present also as a cause of infertility with or without mild sinus problems; 6 to 10 percent of men with obstructive azoospermia have congenital bilateral absence of thevas deferens (CBAVD), which means they were born without the vas deferens; of these,70 percent may have cystic fibrosis or carry a mutation in the cystic fibrosis gene.

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– Noonan syndrome: An inherited condition which can occur in either males or females.In males, this syndrome can cause abnormal gonadal (testicular) function.

– Myotonic dystrophy: An inherited condition with progressive multisystem involvement,resulting in infertility (underdeveloped testes and abnormal sperm production), insome cases.

– Hemachromatosis [Hemochromatosis]: An inherited condition affecting iron storage.Eighty percent of men with hemochromatosis have testicular dysfunction.

– Sickle cell disease: An inherited condition affecting the normal production ofhemoglobin.

– Sex reversal syndrome: A male who has the sex chromosomes of a genetic female (XX, instead of XY), resulting in azoospermia and other characteristics.

– Androgen receptor gene mutations: An inherited condition in which a man is geneticallymale (46,XY), but has infertility due to a defect in receptors for testosterone.

– Chromosomal abnormalities: Men with an extra X sex chromosome, known as Klinefeltersyndrome, often do not produce sperm or produce very low quantities of sperm.

– Chromosome rearrangements: In some persons, there are the usual number of chromo-somes (46) in the nucleus (center) of cells, but rearrangements in the chromosomematerial, where a piece of a chromosome has exchanged places with another, has takenplace; men with either azoospermia or oligospermia have a higher frequency of chro-mosome rearrangements than is found in the general population.

– Deletions in the Y chromosome: In some persons, there are the usual number of chro-mosomes (46) in the body cells, but small sections of the Y chromosome are missing ordeleted; anywhere from 3 to 30 percent of men with either azoospermia or oligosper-mia have deletions in the Y chromosome.

It is important to understand that men who have genetic problems which cause theirinfertility, such as a deletion in the Y chromosome, can pass this problem to their sons,who would also have infertility, if they elect to use their own sperm in achieving apregnancy.

• Anatomical abnormalities: Obstructions of the genital tract can cause infertility by partiallyor totally blocking the flow of seminal fluid. Some of these abnormalities may be of congen-ital (present at birth) origin or the result of a genetic defect. Others could have occurreddue to infection or inflammation of the urogenital tract, surgery that left scar tissue in thegenital tract, or the presence of varicose veins in the scrotum (scrotal varicoceles).

• Immotile cilia syndromes: In this condition, the sperm count is normal but the spermatozoaare nonmotile such as in Kartagener’s syndrome, an inherited disorder.

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• Mitochondrial deletions: Mitochondria are structures in the cell responsible for energy pro-duction. There are actually a set of genes in the mitochondria, separate from the normalchromosome set contained in the nucleus. Recently, it has been discovered that thesegenes, when altered or deleted, can affect a person’s health and/or fertility.

• Liver disease, renal disease, or treatment for seizure disorders

• Other factors: Other factors may arise from the defective delivery of sperm into the femalegenital tract, which could be caused by impotence or premature ejaculation.

How is male factor infertility diagnosed?In addition to a complete medical history and physical examination, diagnostic testing for malefactor infertility may include the following:

• Multiple semen analysis—at least two semen examples are collected on separate days toexamine the semen and sperm for various factors, such as semen volume, consistency, andpH, and the sperm count, motility, and morphology (shape).

• Other tests (to determine the cause of sperm abnormalities or diseases of the male repro-ductive system)

Treatment for male factor infertility:Specific treatment for male factor infertility will be determined by your physician based on:

• your age, overall health, and medical history

• extent of the disease

• your tolerance for specific medications, procedures, or therapies

• expectations for the course of the disease

• your opinion or preference

There is a range of treatment options currently available for male factor infertility. Treatmentmay include:

• Assisted reproductive technologies (ART): This type of treatment may include the following:

• Artificial insemination: Artificial insemination involves the placement of relatively largenumbers of healthy sperm either at the entrance of the cervix or into the partner’suterus, bypassing the cervix, to have direct access to the fallopian tubes.

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• IVF, GIFT, and other techniques: In vitro fertilization (IVF) or gamete intra-fallopiantransfer (GIFT) have been used for the treatment of male infertility. As is the case withartificial insemination, IVF and similar techniques offer the opportunity to prepare spermin vitro, so that oocytes are exposed to an optimal concentration of high-quality, motilesperm.

• Microsurgical fertilization (microinjection techniques such as intracytoplasmic sperminjection, or ICSI): This treatment is used to facilitate sperm penetration by injection ofa single sperm into the oocyte. Fertilization then takes place under the microscope.

• Drug therapy: A small percentage of infertile men have a hormonal disorder that can betreated with hormone therapy. Hormonal imbalances caused by a dysfunction in the mecha-nism of interaction between the hypothalamus, the pituitary gland, and the testes directlyaffect the development of sperm (spermatogenesis). Drug therapy may includegonadotrophin therapy, antibiotics, or another medication deemed appropriate.

• Surgery: Surgical therapy in male infertility is designed to overcome anatomical barriers thatimpede sperm production and maturation or ejaculation. Surgical procedures to remove vari-cose veins in the scrotum (varicocele) can sometimes serve to improve the quality of sperm.

Source: University of Utah Health Sciences Center Web site. Available at: http://www.med.utah.edu/healthinfo/adult/men/infertil.htm

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Appendix 3: Criteria for Causation

*Note: Criteria with an asterisk can be applied to findings of a single study. Other criteria are applied to a series of studies on aparticular topic.

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Criterion Comment

Temporality* Cause must precede effect. This is a necessary condition for causality.

Biological gradient* Causality is supported when higher levels of exposure lead to more severe disease or higher incidence of disease.

Magnitude of the Strong associations are more likely to be causal thanassociation* weak associations.

Consistency If an association is causal, findings should be consistent with other data.

Biological plausibility If an association is causal, it should be plausible in light of scientific knowledge about the biological mechanisms involved.

Coherence A causal interpretation should not conflict with what is known of the natural history and biology of the disease.

Experimental evidence The existence of experimental evidence supports a causal interpretation.

Analogy Analogy with other known associations strengthens the credibility of a causal association.

Appendix 4: Roster of Potential Witnesses

Witness Testimony

Plaintiffs Rumors have been circulating for several years relating the dyecalled Yellow Dye #5 (or tartrazine) in Alpine Fizz to low spermcounts in men who consume the chartreuse-colored drink. Severalchat rooms post messages that put forward the belief that youngmen’s fertility, sexual attractiveness or sexual potency could beadversely affected by drinking Alpine Fizz. For the purposes of thisexercise, let us imagine that a group of heavy Alpine Fizz drinkersmet in one of these chat rooms and discovered that they were allhaving trouble with fertility. All were married, all had been tryingunsuccessfully to get their wives pregnant for more than one year,and all drank at least three cans of Alpine Fizz every day. Theylaunched a Web site and urged people with the same problem tocommunicate with them. After about a year, they had assembledabout 60 couples with infertility problems that they attributed tothe men’s drinking of Alpine Fizz. They hired an impressive legalteam and filed a class action suit.

Defendant The manufacturer of Alpine Fizz, King Kola, claims that there isabsolutely no scientific evidence that tartrazine, caffeine or anyother substance found in Alpine Fizz is related to infertility. All ofthe soft drink’s ingredients are approved by the Food and DrugAdministration (FDA), the federal agency that regulates such mat-ters. The manufacturer claims that the fact that some men drinkAlpine Fizz and are infertile is simply coincidence and that there isno causal association between the two.

Harry G. Walker Mr. Walker is an 80-year-old man who drank Alpine Fizz all his lifeand continues to consume at least two bottles a day. He hasfathered 12 children and is prepared to testify that his soft drinkconsumption has had no effect on his fertility.

Mary Stewart-Swanson Ms. Stewart-Swanson owns Mary’s Deli in Springfield, Connecticut.After a few months of drinking large quantities of Alpine Fizz(more than four cans per day), she began having numerous symp-toms, including rash, diarrhea and shortness of breath. She is pre-pared to testify that after she stopped drinking Alpine Fizz, all hersymptoms disappeared.

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continue

Witness Testimony

Gregory Marchildon Mr. Marchildon is a Madison, Wisconsin, man who claims he is surethat Alpine Fizz lowers sperm count. He is prepared to testify thathe always drinks Alpine Fizz before intercourse, and none of hissexual partners has ever become pregnant.

Michelle Cabano Ms. Cabano is an executive at Bornstein, Burrard, Benson andCabano, a well-known New York City advertising agency. She devel-oped the advertising campaign linking Alpine Fizz to extremesports. Some of these sports (e.g., dirt biking, motocross, moun-tain biking) are reputed to cause low sperm count in men. She isprepared to testify that it may be that men who engage in thesesports are more likely than others to drink Alpine Fizz and that itis the sports activity, not the Alpine Fizz, that is the cause of theinfertility.

Laszlo Nagy Mr. Nagy is the Chief Executive Officer of ABC Chemicals, a NewJersey company that manufactures dyes (including Yellow Dye #5),artificial flavorings and other chemicals for the food industry. He isprepared to testify that more than two million pounds of tartrazineare used every year in medicines, beverages, desserts, processedvegetables and cosmetics. Because a 1986 FDA advisory committeeconcluded that Yellow Dye #5 can cause allergic skin reactions(such as hives and rashes), manufacturers who use tartrazine mustlist it on their labels. However, Mr. Nagy will testify that there hasnever been any evidence that the dye is related to male infertility.

Patrick L. Rodriguez Mr. Rodriguez is a representative of the American CaffeineFoundation. He is prepared to testify that although Alpine Fizzcontains very high levels of caffeine (higher than either Cola Riteor King Kola), there is evidence to suggest that caffeine actuallyincreases the motility and effectiveness of sperm cells.

Janet S. Fang Ms. Fang is Vice President for Public Affairs for the Soft DrinkManufacturers Association of America. She is prepared to testifythat Alpine Fizz has been consumed by millions of people since thedrink was first introduced in the 1950s, and yet King Kola hasnever received a consumer inquiry or complaint about the effectsof Alpine Fizz on male fertility or potency. Her testimony will bebased on the premise that if there were such effects, they wouldhave become apparent by now.

Vanessa Johnson, Ph.D. Dr. Johnson is an organic chemist who specializes in dyes. She willtestify that the chemical structure of tartrazine (commonly known asYellow Dye #5) is similar to that of other dyes, some of which areknown to cause infertility or carcinogenesis. She will also discusssome of the other health effects (e.g., allergy) of Yellow Dye #5.

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Witness Testimony

Pragati Desai, Ph.D. Dr. Desai is a toxicologist who studies the carcinogenic effects ofartificial dyes on animals. She has also studied the effects thatother chemicals have on infertility.

Roger Davis, M.D., Ph.D. Dr. Davis is a physician who is an expert on fertility. He is preparedto testify that he has never encountered a case of AlpineFizz–related infertility in his practice.

Greg Markowicz, DrPH Dr. Markowicz is an epidemiologist who has studied men whodonate sperm at a sperm bank. In his study, Dr. Markowicz askedsperm donors to complete a questionnaire, and one of the ques-tions asked whether they drank Alpine Fizz. His findings indicatethat men who drank one to two 20-oz. bottles of Alpine Fizz perday had a significantly lower sperm count than men who drankAlpine Fizz less frequently. Men who drank three or more bottlesper day had an even lower sperm count.

Gillian McDermott, Ph.D. Dr. McDermott is an epidemiologist who has done a study onpatients at a fertility clinic. She found that the men in her studywho drank one or more 12-oz. cans of Alpine Fizz per day had anaverage sperm count similar to that of men who drank Alpine Fizzless frequently.

Luz Rivera, Ph.D. Dr. Rivera is a clinical psychologist who will testify that in herexperience men who become depressed as a result of infertilitymay turn to stimulants (such as Alpine Fizz) to compensate fortheir feelings of depression.

John Thompson Mr. Thompson is an activist who set up a Web site that collects thestories of men who drank Alpine Fizz and became infertile as aresult.

Harry Humphrey Mr. Humphrey is an herbalist who believes that all synthetic chemi-cals, including Yellow Dye #5, are hazardous to health.

Franz Lichter, M.D. Dr. Lichter, a Swiss radiologist, has done a study comparing malemountain bikers with men who are not mountain bikers. He is pre-pared to testify that mountain bikers have a lower sperm countand less motile sperm than men who are not mountain bikers, andthat mountain bikers are more likely to have abnormalities in theirscrotum. He believes that the observed infertility among the plain-tiffs may be due to their participation in extreme sports (which ismore common among men who drink Alpine Fizz) rather than tothe drink itself.

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continue

Witness Testimony

Georgeanne Parker, Ph.D. Dr. Parker is an epidemiologist who has compiled statistics onaverage sperm counts among U.S. males during every year between1971 and 2001. She also has statistics on the average annual percapita consumption of Alpine Fizz in the United States during thesame period. Her statistics clearly demonstrate that sperm countsdeclined and Alpine Fizz consumption increased over the period inquestion.

Anatoly Pritovich, Ph.D. Dr. Pritovich is a reproductive biologist. He will testify that thesperm count is a measure of the total number of sperm present ina man’s semen, usually recorded in millions of sperm per milliliterof semen. Sperm count varies widely among human males. A nor-mal count is regarded as being greater than 20 million/ml. A manis considered at risk of being infertile if his sperm count is lessthan 20 million/ml of semen. However, some men with low spermcounts are fertile, whereas others with higher counts prove to beinfertile. Dr. Pritovich will testify that a measure of sperm count isnot a completely reliable method of assessing fertility.

Note: All of the individuals and some of the information described in this roster are fictional. They were created for the purposesof this module and any resemblance to real people or situations is purely coincidental.

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Appendix 5: Posttrial Worksheet

1. How likely do you think it is that the correct verdict has been reached? Do you believe, onthe basis of the evidence, that Alpine Fizz causes male infertility?

2. If the losing side were to appeal the verdict, what further evidence would it like to have?

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Description Potential to Infer Causality

Appendix 6: Epidemiologic Study Designs

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RandomizedControlled Trials

Cohort Studies

Case-ControlStudies

Cross-SectionalStudies

Ecologic Studies

Case Series

• Participants with a particulardisease or condition areassigned by randomization to agroup that receives the experi-mental treatment or to a groupthat does not.

• Treated and untreated partici-pants are followed over timeto determine whether theyexperience an outcome (e.g., recovery).

• Exposed and unexposed partici-pants without disease are fol-lowed over time to determinehow many acquire the disease.

• Odds of exposure among per-sons with the disease (cases) iscompared with odds of expo-sure among persons withoutthe disease (controls).

• The status of individuals withrespect to one or more charac-teristics is assessed at onepoint in time.

• The units of analysis are popu-lations or groups of people,rather than individuals.

• Each individual in the popula-tion is characterized by theaverage for the population.

• All participants have the dis-ease (or the exposure).

• Very strong potential to infercausality.

• Randomization reduces potential forselection bias.

• Randomization tends to make thegroups comparable with respect toknown and unknown confoundingvariables.

• Strong potential to infer causality.• Confounding may be a problem

because factors that determinewhether or not a person is exposedmay also be related to the outcome.

• Moderate potential to infer causality.• Confounding may be a problem

because factors that determinewhether or not a person is a casemay also be related to the exposure.

• Selection bias and recall bias areparticular problems.

• Rarely possible to infer causality.• Cannot determine whether exposure

preceded disease.

• Rarely possible to infer causality.• An association observed between

variables on an aggregate level doesnot necessarily represent the associ-ation that exists at an individuallevel.

• Not possible to infer causality.• No comparison group.

alpine fizz and male infertility: a mock trial...1.plaintiffs rumors have been circulating for...

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