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PHARMACEUTICAL

WORLD PHARMA NETWORK July 007

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The medicines that we take have gone throgh at east 10 ears

o testing so that their saet or hmans can be garanteed.However, we are not the on ones that ma be exposed to

these drgs. Hman drgs ma aso aect animas, pants and

bacteria as the can enter the environment via hman excreta

or b disposa o expired medicines via the sewer. This was recognised b

the Eropean union and rom December 006, not on the ecac o

pharmaceticas and their side eects need to be evaated, bt aso the

environmenta impact o the active ingredients. In the present artice, an

otine o the step-wise approach o the Eu-EMEA gideine is given.

BackgRound

In the last 15 to 0 years there have been several reports o pharmaceuticalsin the environment: human and veterinary drugs were detected in river

water and even in drinking water [1, ]. Although reported levels are very

low, eects were observed, with a noteworthy example being hormone

disruption in sh due to the presence o estrogens in the environment. Drug

substances may reach the environment via use or disposal. Patients will usually

excrete a drug or its metabolites, which will then pass to a sewage treatment

plant. There, it may be (partially) degraded, it may adsorb to the sludge or it

may remain in the efuent. Ater processing in the sewage treatment plant,

the sludge is usually incinerated, but it may also be spread on the land, and

then leach into the soil and eventually into the groundwater. In the case

o disposal, depending on the route (drain, household or industrial waste),

pharmaceuticals may enter the groundwater and surace water via a sewage

treatment plant or by leaching rom a landll site.Athogh pharmaceticas and their metaboites in excreta wi be

dited beore entering the sewage treatment pant, and even thogh

eaching rom a and site ma be imited, it shod be kept in mind that

drgs sa are reative stabe ater a , the were deveoped to remain

intact in the hman bod, at east or a certain period. And then, as the were

deveoped with the objective to case a phsioogica eect in hmans,

other organisms ma be sensitive to the mode o action as we.

In 1990, the Eropean Medicines Agenc started a discssion on the

assessment o the risk o pharmaceticas or the environment, resting in

a na gideine that was issed in Jne 006 and has come into operation

in December 006 [3, 4]. The new egisation appies to a new marketing

athorisations with the excsion o vitamins, eectrotes, amino acids,peptides, carbohdrates and ipids; aso vaccines and herba medicina

prodcts are exempted. The pharmacetica indstr anticipated the

naisation o the gideine and severa companies have aread started

environmenta and ecotoxicit stdies with their active ingredients.

The eMea guideline

The EMEA Gideine on the Environmenta Risk Assessment o MedicinaProdcts or Hman use has a step-wise strctre, which is depicted in

Figre 1. Beow, the separate steps are discssed.

Phase i: PRedicTed enviRonMenTal concenTRaTion

and BioaccuMulaTion PoTenTial

The EMEA gideine ocses on the rote o excretion b patients and

does not consider disposa o (expired) drgs or manactrers waste.

The rst step is the estimation o the exposre b cacation o a

Predicted Environmenta Concentration (PEC), based on the maximm

dai dose and the market penetration (detais in Box 1). Whenever the

PEC exceeds the action imit o 0.01 g/l, rther testing is reqired. Thisimit is easi reached: or an active ingredient with a dai dose o mg

per da or more the action imit is exceeded.

In addition to the estimated concentration in the environment, the

potentia o the sbstance to accmate in the environment shod be

evaated. I the sbstance is ipophiic (octano:water partition coecient

= og Kow >4.5), this is an indication that the sbstance ma accmate

in the at tisse o sh and it wi have to be tested or persistence,

bioaccmation potentia and toxicit (PBT). PBT testing is describedin a separate gidance docment that is aso sed or the evaation o

indstria chemicas and pesticides [5].

For some sbstances, sch as those that are known to aect the

reprodction o vertebrate or ower animas at eves beow 0.01 g/l,

BOx 1 CALCuLATiON Of THE PREDiCTED ENviRONMENTAL CONCENTRATiON

(PEC)

PEC surface water = (dose a.i. x F / (Wp x dilution)

PEC = Predicted Environmenta Concentration (mg/l)

Dose a.i. = the maximm recommended dose (mg/person/da)

F = market penetration actor, standard 0.01

Wp = amont o waste water per person per da, standard

Dilution = dition actor, standard 10

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PHARMACEUTICAL

July 007 WORLD PHARMA NETWORK 3

the action imit is not appicabe. The proceed to Phase II testing even

when the PEC is beow the action imit and the specic mode o action

needs to be considered in the risk assessment.

Phase ii, TieR a: Base seT of TesTs

I the PEC exceeds 0.01 g/l, an initia prediction o the risk needs to

be made b execting a primar set o aqatic toxicit and ate tests.

These tests were origina designed or the registration o pesticides,

biocides and indstria chemicas, and gideines are aread avaiabe.The ate o the pharmaceticas in sewage treatment pants is assessed

b biodegradation and adsorption stdies and b a test in which the

dissipation o the sbstance rom natra water and sediment is assessed.

The impact on aqatic organisms needs to be determined b a nmber

o aqatic toxicit tests with agae, daphnids and sh, incding an ear

ie stage toxicit test with sh.

Phase ii, TieR B: fuRTheR evaluaTion of The Risk

Based on the rests o the Tier A testing, the PEC is compared with

the Predicted No Eect Concentrations (PNEC) that were determined

in the toxicit tests. I comparison indicates that there is a risk or theenvironment, rther evaation o the ate and eects o the sbstance

is necessar. From the std with natra water and sediment it wi be

determined whether the pharmacetica migrates rom the water to the

sediment. I so, a toxicit test with sediment organisms sch as mosqitoes

has to be added to the dossier to show whether the deveopment o the

arvae is aected b the drg.

I based on the adsorption std the sbstance is expected to adsorb

strong to the sdge in a sewage treatment pant, this means that it wi be

removed rom the efent. In that case, or when the sbstance is shown

to be readi biodegradabe, the predicted environmenta concentration

can be rened based on this inormation. Frther, the sdge o a sewage

treatment pant to which a pharmacetica has adsorbed ma either be

incinerated, or it ma be sed as ertiiser on the and. In the atter case,the sbstance aso reaches the soi. Thereore, Tier B testing can aso

consist o terrestria compartment testing, sch as transormation in soi,

a pant growth test or an earthworm toxicit test.

I the PEC o a pharmacetica exceeds the trigger vae or testing,

and especia when Tier A rests necessitate Tier B testing, scient

inormation becomes avaiabe to evaate the impact o the compond

on the environment. I it is potentia harm, precationar measres

ma consist o an indication o this risk on the packaging and abeing

indicating how the prodct shod be sed, stored and disposed o.

Registration o a prodct wi not be resed based on the environmenta

risk on.

MeasuRes To liMiT enviRonMenTal Risk

The athorities reqire that the risks are thorogh evaated, bt in

the end hman heath prevais over environmenta saet and thereore

registration wi not be resed. Appropriate abeing o the medicine

NofurthertestingnecessaryAdsorption-Desorption (e.g.OECD 106)

Biodegradation (OECD 301)

Water-sediment study (OECD 308)

AIgal growth inhibition test (OECD 201)

Daphnia reproduction test (OECD 211)

Fish Early Life Stage test (OECD 210)

Activated sludge Respiration Inhibition test (OECD 209)

Phase I

Determine log KowCalculate PEC

Phase I

or effects expected

at

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PHARMACEUTICAL

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is the on measre that can be taken in case there is an indication o

potentia harm. These actions wi on partia redce the exposre o the

environment to the drg: entrance o the drg into the environment via

hman excreta, which is the basis or PEC cacation and risk estimation,

wi remain natered. However, one can imagine that in the tre the

otcome o the risk assessment ma have more conseqences. Easi

biodegradabe medicines ma be preerred over those that are persistent

and potentia harm to the environment. This ma be the consmers

choice, or the athorities ma impose stimating or discoraging

measres.

In addition to imposing this egisation on indstr, other preventive

actions to redce the risk o pharmaceticas in the environment can be

thoght o. Prication o waste water in sewage treatment pants cod

be intensied. However, this wod imp a signicant increase o the

expenses on waste water treatment. More eective, specic attention

cod be given to specic sorces o pharmaceticas in the waste

water, sch as hospitas and homes or the eder. Not on wi totadrg concentrations be reative high in their waste water, in hospitas

aso toxic or ver persistent sbstances are taken and excreted, sch as

ctostatics and X-ra contrast reagents. Separate coection o waste water

rom hospitas and homes or the eder, or temporar rine coection

rom patients at home, wod aow more intensive treatment o a sma

amont o high risk waste.

enviRonMenTal Risk assessMenT ouTside The eu

There is not on concern in Erope abot pharmacetica active

ingredients in the environment: aso the uS and Canada have egisation

on this sbject and in Japan a gideine wi be issed in 008 [6, 7]. InCanada, a seection o existing pharmaceticas aso needs to be tested

or their environmenta risk, whie in Erope and the uS on new actives

and sbstances or which there is an increase in the environmenta

exposre need to be evaated. Each contr aso has its own action imit

and its own approach with regard to which tests shod be perormed

rst. For exampe, the uS trigger vae or testing is 1 g/l, whereas

in Erope it is 0.01 g/l. And whie the Eropean athorities ask or a

worst-case cacation oowed b a base set o tests, the uS approach

starts o with a microbia inhibition test and determination o depetion

mechanisms sch as photosis or metaboism. Depending on the rests

and the expected environmenta concentration, this eads to on one

acte toxicit test or severa chronic stdies, or to the concsion that no

rther tests are reqired. In the tre, at east partia harmonisation othe varios regations ma be desirabe.

For veterinar medicines the gideines aread nderwent a

harmonisation process, and this ma be taken as a mode or harmonisation

o gideines or hman medicines.

conclusion

With the adoption o a Eropean gideine or the environmenta risk

assessment o hman medicines, the environment is shown as a potentia

victim o or se o pharmaceticas. Even thogh the intervention

b the athorities remains restricted, the new regations wi ead to

a better nderstanding o the risk and the wi enhance awareness omanactrers and sers o the impact o drgs on the environment.

Improper se and disposa o hman medicine se wi be redced. The

step-wise approach o the gideine provides the indstr with cear

gidance on whether and which tests need to be perormed. However,

comparison with other contries regations shows that more than one

approach can be chosen.

References:

[1] Richardson M.l. and Bowron J.M. (1985). The ate o pharmaceticas in the

aqatic environment. Jornal o Pharmacy and Pharmacology (37): 1-1.

[] Haing-Srensen B., Nors Niesen S., lanzk P.F., Ingersev F., Hoten ltzhot

H.C. and Jrgensen (1998). Occrrence, ate and eects o pharmacetica

sbstances in the environment A review. Chemosphere 36 (): 57-393.

[3] Gideine on the environmenta risk assessment o medicina prodcts or

hman se (Eropean Medic ines Agenc, Jne 1, 006) www.emea.e.int

[4] Directive 001/83/EC o the Eropean Pariament and o the conci o 6

November 001 on the commnit code reating to medicina prodcts or

hman sed, as amended (Artice 8(3)).

[5] Eropean Chemicas Brea (003) Technica Gidance Docment in spport

o Commission Directive 93/67/EEC on Risk Assessment or new notied

sbstances, Commission Regation (EC) No 1488/94 on Risk Assessment orexisting sbstance and Directive 98/8/EC o the Eropean Pariament and o

the Conci concerning the pacing o biocida prodcts on the market.

[6] Environmenta Assessment o Hman Drg and Bioogics Appications

(J 1998) www.da.gov./cder/gidance/1730n.pd

[7] www.heathcanada.gc.ca/eii; www.hc-sc.gc.ca/ewhsemt/

contaminants/person/eva/index e.htm

Contact:

Erik Hamminga

Sales & Marketing Manager Pharmaceuticals

E-mail: erik.hamminga@notox.nl

BrpyBRigiTTe van nooRloosBrigitte van Nooroos gradated with an

MSc in Chemistr rom the universit o

Nijmegen, The Netherands. Since 000

she has spervised environmenta ate

and metaboism stdies at NOTOX in s-

Hertogenbosch, The Netherands. Initia

the work main concerned agrochemicas

and indstria chemicas, bt now aso

pharmaceticas have become a major area

o environmenta testing. Brigitte was asoinvoved in dossier preparation o high prodction vome chemicas

and the risk evaation o agrochemicas or the Dtch Board or the

Athorisation o Pesticides (CTB).